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CLA (CONJUGATED LINOLEIC ACID)



Table of Contents
image Conjugated linoleic acid: A powerful anticarcinogen from animal fat sources
image Conjugated linoleic acid and atherosclerosis in rabbits
image Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid
image Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells
image Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat
image Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat
image Effect of cheddar cheese consumption on plasma conjugated linoleic acid concentrations in men
image Differential stimulatory and inhibitory responses of human MCF-7 breast cancer cells to linoleic acid and conjugated linoleic acid in culture
image Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells
image Inhibition of Listeria monocytogenes by fatty acids and monoglycerides
image Recognition of cervical neoplasia by the estimation of a free-radical reaction product (octadeca-9,11-dienoic acid) in exfoliated cells
image Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection
image Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid
image Conjugated linoleic acid and atherosclerosis in rabbits
image Conjugated linoleic acid is a growth factor for rats as shown by enhanced weight gain and improved feed efficiency
image Cows' milk fat components as potential anticarcinogenic agents
image Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes
image Effects of dietary conjugated linoleic acid on lymphocyte function and growth of mammary tumors in mice
image Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice
image Lymphatic recovery, tissue distribution, and metabolic effects of conjugated lioleic acid in rats
image Proliferative responses of normal human mammary and MCF-7 breast cancer cells to linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture
image Conjugated linoleic acid modulates hepatic lipid composition in mice
image Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion
image The efficacy of conjugated linoleic acid in mammary cancer prevention is independent of the level or type of fat in the diet
image Dietary modifiers of carcinogenesis
image Effects of C18 fatty acid isomers on DNA synthesis in hepatoma and breast cancer cells
image Effect of timing and duration of dietary conjugated linoleic acid on mammary cancer prevention
image The role of phenolics, conjugated linoleic acid, carnosine, and pyrroloquinoline quinone as nonessential dietary antioxidants
image Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atharosclerosis in hypercholasterolemic hamsters

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Conjugated linoleic acid: A powerful anticarcinogen from animal fat sources

Ip C.; Scimeca J.A.; Thompson H.J.
Department of Surgical Oncology, Roswell Park Center Institute, Elm and Carlton Streets, Buffalo, NY 14263 USA
CANCER (USA) , 1994, 74/3 (1050-1054)

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid, which is found preferentially in dairy products and meat. Preliminary studies indicate that CLA is a powerful anticarcinogen in the rat mammary tumor model with an effective range of 0.1-1% in the diet. This protective effect of CLA is noted even when exposure is limited to the time of weaning to carcinogen administration. The timing of this treatment corresponds to maturation of the mammary gland to the adult stage, suggesting that CLA may have a direct effect in reducing the cancer risk of the target organ. Of the vast number of naturally occurring substances that have been demonstrated to have anticarcinogenic activity in experimental models, all but a handful of them are of plant origin. Conjugated linoleic acid is unique because it is present in food from animal sources, and its anticancer efficacy is expressed at concentrations close to human consumption levels.



Conjugated linoleic acid and atherosclerosis in rabbits

Lee K.N.; Kritchevsky D.; Pariza M.W.
Food Research Institute, Dept. Food Microbiology/Toxicology, University of Wisconsin-Madison, 1925 Willow Drive, Madison, WI 53706 USA
Atherosclerosis (Ireland), 1994, 108/1 (19-25)

Conjugated linoleic acid (CLA) consists of a series of positional and geometric dienoic isomers of linoleic acid that occur naturally in foods. CLA exhibits antioxidant activity in vitro and in vivo. To assess the effect of CLA on atherosclerosis, 12 rabbits were fed a semi-synthetic diet containing 14% fat and 0.1% cholesterol for 22 weeks. For 6 of these rabbits, the diet was augmented with CLA (0.5 g CLA/rabbit per day). Blood samples were taken monthly for lipid analysis. By 12 weeks total and LDL cholesterol and triglycerides were markedly lower in the CLA-fed group. Interestingly, the LDL cholesterol to HDL cholesterol ratio and total cholesterol to HDL cholesterol ratio were significantly reduced in CLA-fed rabbits. Examination of the aortas of CLA-fed rabbits showed less atherosclerosis.



Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid

Chin S.F.; Storkson J.M.; Liu W.; Albright K.J.; Pariza M.W.
Food Microbiology/Toxicology Dept.,
Food Research Institute, University of Wisconsin, Madison, WI 53706 USA
J. NUTR. (USA) , 1994, 124/5 (694-701)

Conjugated linoleic acid (CLA) is an anticarcinogen in several model animal systems. Conjugated linoleic acid occurs naturally in food and is present at higher concentrations in products from ruminant animals. Given that certain rumen microorganisms produce CLA from free linoleic acid, we studied the effect of feeding free or esterified linoleic acid on tissue CLA concentrations using conventional and germ-free rats. Conventional rats were fed a 5% (wt/wt) corn oil control diet alone or supplemented with 5% free linoleic acid or 8.63% corn oil (equivalent to 5% linoleic acid in triglyceride). Germ-free rats were fed autoclavable nonpurified diet alone or supplemented with 5% free linoleic acid. Analyses of CLA concentrations were performed on lipids extracted from liver, lung, kidney, skeletal muscle and abdominal adipose tissue, and on liver phospholipid and neutral lipid fractions. Tissue CLA concentrations were higher in conventional rats fed free linoleic acid (the major isomers were cis-9, trans-11 and trans-9, cis-11) than in control animals. Conjugated linoleic acid concentrations in free linoleic acid-fed rats were maximal at 4 wk, and levels were 5-10 times higher than those of controls. Elevated CLA concentrations were also observed in liver phospholipid and neutral lipid fractions. In contrast, CLA concentrations in the tissues of germ-free rats were not affected by diet. Feeding the corn oil-fortified diet to conventional rats did not increase CLA concentration in the tissues. We conclude that the intestinal bacterial flora of rats is capable of converting free linoleic acid (but not linoleic acid esterified in triglycerides) to cis-9, trans-11 and trans-9, cis-11 CLA isomers.



Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells

Shultz TD; Chew BP; Seaman WR; Luedecke LO

Cancer Lett (NETHERLANDS) Apr 15 1992, 63 (2) p125-33,

The effects of physiologic concentrations of conjugated linoleic acid (CLA) and beta-carotene were assessed on human (M21-HPB, malignant melanoma; HT-29, colorectal; MCF-7, breast) cancer cells. The incubation of cancer cells with CLA showed significant reductions in proliferation (18-100%) compared to control cultures. M21-HPB and MCF-7 cell mortality was dose- and time-dependent. beta-Carotene was inhibitory to breast cells only. MCF-7 cells supplemented with CLA incorporated significantly less [3H]leucine (45%), [3H]uridine (63%) and [3H]thymidine (46%) than control cultures. M21-HPB and HT-29 cells supplemented with CLA incorporated less [3H]leucine (25-30%). These in vitro results suggest that CLA and beta-carotene may be cytotoxic to human cancer cells in vivo.



Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat

Ip C; Singh M; Thompson HJ; Scimeca JA

Cancer Res (UNITED STATES) Mar 1 1994, 54 (5) p1212-5,

Conjugated linoleic acid (CLA) is a collective term which refers to a mixture of positional and geometric isomers of linoleic acid. It is naturally occurring in meat and dairy products. We have previously reported (Ip, C., Chin, S. F., Scimeca, J. A., and Pariza, M. W. Cancer Res., 51: 6118-6124, 1991) that 1% CLA in the diet suppressed mammary carcinogenesis in rats given a high dose (10 mg) of 7,12-dimethylbenz(a)anthracene. In the present study, dietary CLA between 0.05 and 0.5% was found to produce a dose-dependent inhibition in mammary tumor yield when fed chronically to rats treated with a lower dose (5 mg) of 7,12-dimethylbenz(a)anthracene. Short-term CLA feeding for 5 weeks, from weaning to the time of carcinogen administration at 50 days of age, also offered significant protection against subsequent tumor occurrence. This period corresponds to maturation of the mammary gland to the adult stage in the rat. The inhibitory response to short-term CLA exposure was observed with the use of 2 different carcinogens: 7,12-dimethylbenz(a)anthracene and methylnitrosourea. The fact that CLA was protective in the methylnitrosourea model suggests that it may have a direct modulating effect on susceptibility of the target organ to neoplastic transformation. The proliferative activity of the mammary epithelium was assessed by the incorporation of bromodeoxyuridine. Immunohistochemical staining results showed that CLA reduced the labeling index of the lobuloalveolar compartment, but not that of the ductal compartment of the mammary tree. Since the lobuloalveolar structures are derived from the terminal end buds which are the sites of carcinogenic transformation, the above finding is consistent with the bioassay data of tumor inhibition. Thus, changes in gland development and morphogenesis may be a locus of action of CLA in modulating mammary carcinogenesis. CLA is a unique anticarcinogen because it is present in foods from animal sources. Furthermore, its efficacy in cancer protection is manifest at dietary concentrations which are close to the levels consumed by humans.



Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat

CANCER RES. (USA) , 1994, 54/5 (1212-1215)

Conjugated linoleic acid (CLA) is a collective term which refers to a mixture of positional and geometric isomers of linoleic acid. It is naturally occurring in meat and dairy products. We have previously reported (Ip, C., Chin, S.F.,Scimeca, J. A., and Pariza, M.W.Cancer Res., 51:6118- 6124, 1991) that 1% CLA in the diet suppressed mammary carcinogenesis in rats given a high dose (10 mg) of 7,12-dimethylbenz(a)anthracene. In the present study, dietary CLA between 0.05 and 0.5% was found to produce a dose-dependent inhibition in mammary tumor yield when fed chronically to rats treated with a lower dose (5 mg) of 7,12-dimethylbenz(a)anthracene. Short term CLA feeding for 5 weeks, from weaning to the time of carcinogen administration at 50 days of age, also offered significant protection against subsequent tumor occurrence. This period corresponds to maturation of the mammary gland to the adult stage in the rat. The inhibitory response to short-term CLA exposure was observed with the use of 2 different carcinogens: 7,12- dimethylbenz(a)anthracene and methylnitrosourea. The fact that CLA was protective in the methylnitrosourea model suggests that it may have a direct modulating effect on susceptibility of the target organ to neoplastic transformation. The proliferative activity of the mammary epithelium was assessed by the incorporation of bromodeoxyuridine. Immunohistochemical staining results showed that CLA reduced the labeling index of the lobuloalveolar compartment, but not that of the ductal compartment of the mammary tree. Since the lobuloalveolar structures are derived from the terminal end buds which are the sites of carcinogenic transformation, the above finding is consistent with the bioassay data of tumor inhibition. Thus, changes in gland development and morphogenesis may be a locus of action of CLA in modulating mammary carcinogenesis. CLA is a unique anticarcinogen because it is present in foods from animal sources. Furthermore, its efficacy in cancer protection is manifest at dietary concentrations which are close to the levels consumed by humans.



Effect of cheddar cheese consumption on plasma conjugated linoleic acid concentrations in men

NUTR. RES. (USA) , 1994, 14/3 (373-386)

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid with conjugated double bonds. Conjugated linoleic acid has anticarcinogenic properties and has been identified in human biological fluids and adipose tissue. The origin of CLA in humans is not known, but diet may be contributory. A variety of cheeses, including Cheddar, are good sources of CLA. To investigate the effect of Cheddar cheese consumption (112 g/day) on plasma phospholipid-esterified CLA concentrations, nine healthy men were studied. Cheddar cheese was added to their daily diets for four weeks. Three-day diet records and fasting blood samples were obtained. Protein and total fat intakes increased significantly during dietary intervention. Plasma CLA was significantly higher following Cheddar cheese feeding, exceeding by 19-27% the concentrations observed initially and following intervention. The molar ratio of CLA to linoleic acid also increased significantly following dietary intervention. Plasma concentrations of linoleic and arachidonic acids, cholesterol and phospholipids were not affected by cheese feeding. Since CLA may represent a protective factor against cancer, further study identifying dietary sources and the health benefits of CLA are warranted.



Differential stimulatory and inhibitory responses of human MCF-7 breast cancer cells to linoleic acid and conjugated linoleic acid in culture

ANTICANCER RES. (Greece) , 1992, 12/6 B (2143-2145)

Consumption of dietary fat has been linked to the high incidence of certain cancers. However, recent research has stimulated interest in conjugated linoleic acid (CLA), a newly recognized anticarcinogenic fatty acid. Human MCF-7 breast cancer cells were incubated for 12 d in ous concentr ations (1.78 - 7.14 x 10-5 M) of linoleic acid (LA) or CLA. Linoleic acid initially stimulated MCF-7 cell growth with an optimal effect at concentrations of 3.57 - 7.14 x 10-5 M, but was inhibitory at similar concentrations after 8 and 12 d of incubation. In contrast, CLA was inhibitory to cancer cell growth at all concentrations and times tested. Cell growth inhibition by CLA was dose and time - dependent. Growth retardation at the prescribed LA and CLA concentrations ranged, respectively, from 4 to 33% and 54 to 100% following 8 to 12 d of treatment. At similar LA and CLA concentrations, cytostatic and cytotoxic effects of CLA were more pronounced (8 - 81%) than LA. These in vitro results suggest that CLA is cytotoxic to MCF-7 cells.



Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells

CANCER LETT. (Ireland) , 1992, 63/2 (125-133)

The effects of physiologic concentrations of conjugated linoleic acid (CLA) and beta-carotene were assessed on human (M21-HPB malignant melanoma; HT-29 colorectal; MCF-7 breast) cancer cells. The incubation of cancer cells with CLA showed significant reductions in proliferation (18-100%) compared to control cultures. M21-HPB and MCF-7 cell mortality was dose- and time-dependent. beta-Carotene was inhibitory to breast cells only. MCF-7 cells supplemented with CLA incorporated significantly less (3H)leucine (45%) (3H)uridine (63%) and (3H)thymidine (46%) than control cultures. M21-HPB and HT-29 cells supplemented with CLA incorporated less (3H)leucine (25-30%). These in vitro results suggest that CLA and beta-carotene may be cytotoxic to human cancer cells in vivo.



Inhibition of Listeria monocytogenes by fatty acids and monoglycerides

APPL. ENVIRON. MICROBIOL. (USA) , 1992, 58/2 (624-629)

Fatty acids and monoglycerides were evaluated in brain heart infusion broth and in milk for antimicrobial activity against the Scott A strain of Listeria monocytogenes. C(12:0), C(18:3), and glyceryl monolaurate (monolaurin) had the strongest activity in brain heart infusion broth and were bactericidal at 10 to 20 microg/ml, whereas potassium (K)-conjugated linoleic acids and C(18:2) were bactericidal at 50 to 200 microg/ml. C(14:0), C(16:0), C(18:0), C(18:1), glyceryl monomyristate, and glyceryl monopalmitate were not inhibitory at 200 microg/ml. The bactericidal activity in brain heart infusion broth was higher at pH 5 than at pH 6. In whole milk and skim milk, K-conjugated linoleic acid was bacteriostatic and prolonged the lag phase especially at 4degreeC. Monolaurin inactivated L. monocytogenes in skim milk at 4degreeC, but was less inhibitory at 23degreeC. Monolaurin did not inhibit L. monocytogenes in whole milk because of the higher fat content. Other fatty acids tested were not effective in whole or skim milk. Our results suggest that K-conjugated linoleic acids or monolaurin could be used as an inhibitory agent against L. monocytogenes in dairy foods.



Recognition of cervical neoplasia by the estimation of a free-radical reaction product (octadeca-9,11-dienoic acid) in exfoliated cells

CLIN. CHIM. ACTA (NETHERLANDS) , 1987, 163/2 (149-152)

lar ratio between a diene-conjugated linoleic-acid isomer (18 : 2(9,11)) and the parent linoleic acid (18 : 2(9,12)), both esterified as phospholipids, was significantly different in exfoliated cells from normal cervices and from cervices with colposcopic and cytological evidence of precancer. The measurement may provide a simple and perhaps improved alternative to cytological screening.



Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection

BIOCHEM. BIOPHYS. RES. COMMUN. (USA) , 1994, 198/3 (1107-1112)

The ability of conjugated linoleic acid to prevent endotoxin-induced growth suppression was examined. Mice fed a basal diet or diet with 0.5% fish oil lost twice as much body weight after endotoxin injection than mice fed conjugated lineoleic acid. By 72 hours post injection, mice fed conjugated linoleic acid had body weights similar to vehicle injected controls; however, body weights of basal and fish oil fed mice injected with endotoxin were reduced. Conjugated linoleic acid prevented anorexia from endotoxin injection. Splenocyte blastogenesis was increased by conjugated linoleic acid.



Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid

J. NUTR. (USA) , 1994, 124/5 (694-701)

Conjugated linoleic acid (CLA) is an anticarcinogen in several model animal systems. Conjugated linoleic acid occurs naturally in food and is present at higher concentrations in products from ruminant animals. Given that certain rumen microorganisms produce CLA from free linoleic acid, we studied the effect of feeding free or esterified linoleic acid on tissue CLA a 5% (wt/wt) corn oil control diet alone or supplemented with 5% free linoleic acid or 8.63% corn oil (equivalent to 5% linoleic acid in triglyceride). Germ-free rats were fed autoclavable nonpurified diet alone or supplemented with 5% free linoleic acid. Analyses of CLA concentrations were performed on lipids extracted from liver, lung, kidney, skeletal muscle and abdominal adipose tissue, and on liver phospholipid and neutral lipid fractions. Tissue CLA concentrations were higher in conventional rats fed free linoleic acid (the major isomers were cis-9, trans-11 and trans-9, cis- 11) than in control animals. Conjugated linoleic acid concentrations in free linoleic acid-fed rats were maximal at 4 wk, and levels were 5-10 times higher than those of controls. Elevated CLA concentrations were also observed in liver phospholipid and neutral lipid fractions. In contrast, CLA concentrations in the tissues of germ-free rats were not affected by diet. Feeding the corn oil-fortified diet to conventional rats did not increase CLA concentration in the tissues. We conclude that the intestinal bacterial flora of rats is capable of converting free linoleic acid (but not linoleic acid esterified in triglycerides) to cis-9, trans-11 and trans-9, cis-11 CLA isomers.



Conjugated linoleic acid and atherosclerosis in rabbits

ATHEROSCLEROSIS (Ireland) , 1994, 108/1 (19-25)

Conjugated linoleic acid (CLA) consists of a series of positional and geometric dienoic isomers of linoleic acid that occur naturally in foods. CLA exhibits antioxidant activity in vitro and in vivo. To assess the effect of CLA on atherosclerosis, 12 rabbits were fed a semi-synthetic diet containing 14% fat and 0.1% cholesterol for 22 weeks. For 6 of these rabbits, the diet was augmented with CLA (0.5 g CLA/rabbit per day). Blood samples were taken monthly for lipid analysis. By 12 weeks total and LDL cholesterol and triglycerides were markedly lower in the CLA-fed group. Interestingly, the LDL cholesterol to HDL cholesterol ratio and total cholesterol to HDL cholesterol ratio were significantly reduced in CLA-fed rabbits. Examination of the aortas of CLA-fed rabbits showed less atherosclerosis.



Conjugated linoleic acid is a growth factor for rats as shown by enhanced weight gain and improved feed efficiency

J. NUTR. (USA) , 1994, 124/12 (2344-2349)

We studied the effect of conjugated linoleic acid (CLA) on rat development and growth. Primigravid female Fischer rats were fed control or CLA- supplemented (0.25% or 0.5% CLA) diets during gestation and/or lactation. Conjugated linoleic acid was incorporated into milk fat and tissue lipids proportional to the level of CLA fed and the duration of CLA feeding. Conjugated linoleic acidas incorporated into fetal and neonatal tissues; it did not affect litter size nor induce apparent abnormalities. To the contrary, feeding CLA to the dams during gestation and lactation improved the postnatal body weight gain of pups (P < 0.05), measured on d 10 of lactation. Pups that continued to receive the CLA-supplemented diet after weaning had significantly greater body weight gain and improved feed efficiency relative to control animals (P < 0.05).



Cows' milk fat components as potential anticarcinogenic agents

Journal of Nutrition (USA) , 1997, 127/6 (1055-1060)

The optimum approach to conquering cancer is prevention. Although the human diet contains components which promote cancer, it also contains components with the potential to prevent it. Recent research shows that milk fat contains a number of potential anticarcinogenic components including conjugated linoleic acid, sphingomyelin, butyric acid and ether lipids. Conjugated linoleic acid inhibited proliferation of human malignant melanoma, colorectal, breast and lung cancer cell lines. In animals, it reduced the incidence of chemically induced mouse epidermal tumors, mouse forestomach neoplasia and aberrant crypt foci in the rat colon. In a number of studies, conjugated linoleic acid, at near-physiological concentrations, inhibited mammary tumorigenesis independently of the amount and type of fat in the diet. In vitro studies showed that the milk phospholipid, sphingomyelin, through its biologically active metabolites ceramide and sphingosine, participates in three major antiproliferative pathways influencing oncogenesis, namely, inhibition of cell growth, and induction of differentiation and apoptosis. Mice fed sphingomyelin had fewer colon tumors and aberrant crypt foci than control animals. About one third of all milk triacylglycerols contain one molecule of butyric acid, a potent inhibitor of proliferation and inducer of differentiation and apoptosis in a wide range of neoplastic cell lines. Although butyrate produced by colonic fermentation is considered important for colon cancer protection, an animal study suggests dietary butyrate may inhibit mammary tumorigenesis. The dairy cow also has the ability to extract other potential anticarcinogenic agents such as beta- carotene, beta-ionone and gossypol from its feed and transfer them to milk. Animal studies comparing the tumorigenic potential of milk fat or butter with linoleic acid-ricless tumor development with dairy products.



Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes

Proceedings of the National Academy of Sciences of the United States of America (USA) , 1997, 94/8 (4182-4187)

Our recent data show that in cardiac myocytes polyunsaturated fatty acids (PUFAs) are antiarrhythmic. They reduce I(Na), shorten the action potential, shift the threshold for excitation to more positive potentials, and prolong the relative refractory period. In this study we use patch-clamp techniques in whole-cell mode and confocal Ca2+ imaging to examine the effects of PUFAs on the voltage-gated L-type Ca2+ current (I(Ca,L)), elementary sarcoplasmic reticulum Ca2+-release events (Ca2+-sparks), and (Ca2+)(i) transients in isolated rat ventricular myocytes. Extracellular application of eicosapentaenoic acid (EPA; C20:5 n - 3) produced a prompt and reversible concentration-dependent suppression of I(Ca,L). The concentration of EPA to produce 50% inhibition of I(Ca) was 0.8 microM in neonatal rat heart cells and 2.1 microM in adult ventricular myocytes. While the EPA induced suppression of I(Ca,L), it did not significantly alter the shape of the current-voltage relation but did produce a small, but significant, negative shift of the steady-state inactivation curve. The inhibition of I(Ca,L) was voltage- and time-dependent, but not use- or frequency-dependent. Other PUFAs, such as docosahexaenoic acid, arachidonic acid, linolenic acid, linoleic acid, conjugated linoleic acid, and eicosatetraynoic acid had similar effects on I(Ca,L) as EPA. All-trans-retinoic acid, which had been shown to suppress induced arrhythmogenic activity in rat heart cells, also produced a significant inhibition of I(Ca,L). The saturated stearic acid and sarcoplasmic reticulum Ca2+-release underlie many cardiac arrhythmias, we examined the effects of EPA on I(Ca,L) and Ca2+-sparks. While EPA suppressed both, it did not change the temporal or spatial character of the Ca2+-sparks, nor did it alter the ability of I(Ca,L) to trigger Ca2+- sparks. We conclude that PUFAs may act as antiarrhythmic agents in vivo in normal and Ca2+-overloaded cells principally because they reduce Ca2+ entry by blocking I(Ca,L). Furthermore, PUFAs act directly to decrease I(Na) and I(Ca,L), but indirectly to reduce the (Ca2+)(i) transients and (Ca2+)(i)-activated membrane current. Although a negative inotropic action is associated with application of PUFAs, it is clear that by reducing I(Ca,L), I(Na) and Ca2+-sparks, PUFAs can reduce spontaneous extrasystoles in the heart. The mechanisms by which PUFAs act are discussed.



Effects of dietary conjugated linoleic acid on lymphocyte function and growth of mammary tumors in mice

Anticancer Research (Greece) , 1997, 17/2 A (987-993)

We studied the effects of conjugated linoleic acid (CLA) on lymphocyte function and growth of a transplantable murine mammary tumor. In experiment 1, eig(n = 8/group) were fed 0.1%, 0.3% or 0.9% CLA for 3 or 6 wk. Lymphocyte proliferation, interleukin-2 production and lymphocyte cytotoxicity were assessed using splenic lymphocytes. Plasma CLA concentrations increased in a dose-dependent manner with CLA feeding. Lymphocyte proliferation in mice fed 0.3% and 0.9% CLA was enhanced in phytohemagglutinin-induced but not in concanavalin A- or lipopolysaccharide-stimulated cultures. Production of IL-2 also was stimulated by CLA. In contrast, CLA had no effect on lymphocyte cytotoxicity. In experiment 2, mice (n = 20/treatment) were fed the same diets for 2 wk before being infused with 1 x 106 WAZ-2T metastatic mammary tumor cells into the right inguinal mammary gland. Tumor volume and latency were recorded for 45 d. Dietary CLA did not affect mammary tumor growth. Tumor latency, tumor incidence and tumor lipid peroxidation activity also were unaffected by CLA. Body weight and feed intake were similar among treatments. Therefore, dietary CLA modulated certain aspects of the immune defense but had no obvious effect on the growth of an established, aggressive mammary tumor.



Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice

Anticancer Research (Greece) , 1997, 17/2 A (969-973)

Conjugated linoleic acid (CLA), which is mainly derived from dairy products, has been shown both in vitro and in animal models to have strong anti-tumor activity. Particular effects were observed on the growth and metastatic spread of transplantable mammary tumors. In this study, we examined the effect of dietary CLA on the growth of human breast adenocarcinoma cells in severe combined immunodeficient (SCID) mice. Mice were fed 1% CLA for two weeks prior to subcutaneous inoculation of 107 MDA-MB468 cells and throughout the wth by 73% and 30% at 9 and 14 weeks post-inoculation, respectively. Moreover, CLA completely abrogated the spread of breast cancer cells to lungs, peripheral blood, and bone marrow. These results indicate the ability of dietary CLA to block both the local growth and systemic spread of human breast cancer via mechanisms independent of the host immune system.



Lymphatic recovery, tissue distribution, and metabolic effects of conjugated lioleic acid in rats

Journal of Nutritional Biochemistry (USA) , 1997, 8/1 (38-43)

Apparent lymphatic recovery of conjugated linoleic acid (CLA) in rats was considerably lower than for linoleic acid, approximately 55% versus 80% for 24 hr, although the distribution in lymph lipoproteins was similar. Not all the CLA constituents were recovered equally, and more tt-isomers were recovered than ct- or tc-isomers in relation to the composition of CLA given. When rats were fed CLA or linoleic acid at the dietary level of 1% for 2 weeks, there were detectable differences in the incorporation of CLA in various tissues, and adipose tissue and lung contained the highest proportion, whereas a limited amount was incorporated into the brain. In general, 9c, 11t/9t,11c isomers were the predominant CLA followed by tt-isomers. Also, CLA was differently incorporated into individual phospholipids in the liver. No effects were observed on serum and liver lipid levels, but the concentration of prostaglandin E2 (PGE2) in serum anhe for mer was statistically significant. CLA did not increase tissue TBA values. Thus, the metabolic effect of CLA may not be attributed to a single entity.



Proliferative responses of normal human mammary and MCF-7 breast cancer cells to linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture

Anticancer Research (Greece) , 1997, 17/1 A (197-203)

Potential mechanisms for the stimulation or inhibition of cell growth by linoleic acid (LA) and conjugated linoleic acid (CLA) were investigated by using eicosanoid linoleic acid (CLA) were investigated by using eicosanoid synthesis inhibitors. Normal human mammary epithelial cells (HMEC) and MCF-7 breast cancer cells were incubated in serum-free medium supplemented with LA or CLA and cyclooxygenase (indomethacin; INDO) or lipoxygenase (nordihydroguaiaretic acid; NDGA) inhibitors. Linoleic acid stimulated the growth and (3H)thymidine incorporation of normal HMEC and MCF-7 cancer cells, while CLA was inhibitory. Supplementation with LA increased intracellular lipid peroxide concentrations in normal HMEC and MCF-7 cancer cells, whereas CLA did not affect lipid peroxide formation. Normal HMEC and MCF-7 cells supplemented with LA and INDO or NDGA resulted in growth inhibition. The treatment of normal HMEC with CLA and INDO or NDGA, and MCF-7 cells with CLA and INDO stimulated cell growth. However, the addition of CLA and NDGA to MCF-7 cells resulted in synergistic growth suppression suggesting that CLA effects were mediated through lipoxygenase inhibition. Although NDGA was more inhibitory of cell growth in the presence of LA or CLA than INDO, growth was associate with both prostaglandin and leukotriene production. Additional studies are warranted to elucidate the mechanism(s)

whereby LA or CLA affect breast cell growth.



Conjugated linoleic acid modulates hepatic lipid composition in mice

Lipids (USA) , 1997, 32/2 (199-204)

Conjugated linoleic acid (CLA) is a chemoprotective fatty acid that inhibits mammary, colon, forestomach, and skin carcinogenesis in experimental animals. We hypothesize that the ubiquitous chemoprotective actions of dietary CLA in extrahepatic tissues are dependent upon its role in modulating fatty acid composition and metabolism in liver, the major organ for lipid metabolism. This study begins to evaluate the role of CLA in lipid metabolism by determining the modulation of fatty acid composition by CLA. Female SENCAR mice were fed semipurified diets containing 0.0% (Diet A), 0.5% (Diet B), 1.0% (Diet C), or 1.5% (Diet D) CLA (by weight) for six weeks. Mice fed Diets B, C, and D exhibited lower body weights and elevated amounts of extractable total lipid in livers compared with mice fed diets without CLA (Diet A). Analyses of the fatty acid composition of liver by gas chromatography revealed that dietary CLA was incorporated into neutral and phospholipids at the expense of linoleate in Diets B, C, and D; oleate increased and arachidonate decreased in neutral lipids of CLA diet groups. In addition, increasing dietary CLA was associated with reduced linoleate in hepatic phospholipids. In an in vitro assay, CLA was desaturated to an unidentified 18:3 product to a similar extent as linoleate conversion to gamma- linolenate (9.88, and 13.63%, respectively). These data suggest that CLA may affect metabolic interconversion of fatty acids in liver that may ultimately result in modified fatty acid composition and arachidonate-derived eicosanoid production in extrahepatic tissues. In addition to determining how dietary CLA modulates eicosanoid synthesis, further work is needed to identify enzymatic products that may result from desaturation of CLA.



Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion

Nutrition and Cancer (USA) , 1996, 26/2 (149-157)

The fatty acid derivative conjugated dienoic linoleate (CLA) has been shown to inhibit initiation and postinitiation stages of carcinogenesis in several experimental animal models. The goal of the present study was to determine the role of increasing levels of dietary CLA in mouse skin tumor promotion elicited by 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice were fed control (no CLA) diet during initiation, then switched to diets containing 0.0%, 0.5%, 1.0%, or 1.5% (wt/wt) CLA during skin tumor promotion by TPA. Body weights of mice fed 0.5%, 1.0%, or 1.5% CLA were similar to each other but were significantly lower (p < 0.05) than weights of mice fed no CLA (0.0%) throughout promotion. A reduction in papilloma incidence was observed in mice fed 1.5% CLA from Weeks 8 to 24 compared with mice fed diets containing 0.0-1.0% CLA (p < 0.05). Twenty-four weeks after tumor promotion was begun, diets containing 1.0% and 1.5% CLA inhibited tumor yield (4.94 and 4.35 tumors/mouse, respectively) compared with diets without CLA (0.0% CLA, 6.65 tumors/mouse, p < 0.05) or 0.5% CLA (5.92 tumors/mouse, p < 0.05). These data indicate that CLA inhibits tumor promotion in a manner that is independent of its anti-initiator activity. Further studies are warranted in identifying cellular mechanisms that are likely to be involved with the antipromoter effects of CLA.



The efficacy of conjugated linoleic acid in mammary cancer prevention is independent of the level or type of fat in the diet

Carcinogenesis (United Kingdom) , 1996, 17/5 (1045-1050)

The objective of the present study was to investigate whether the anticarcinogenic activity of conjugated linoleic acid (CLA) is affected by the amount and composition of dietary fat consumed by the host. Because the anticancer agent of interest is a fatty acid, this approach may provide some insight into its mechanism of action, depending on the outcome of these fat feeding experiments. For the fat level experiment, a custom formulated fat blend was used that simulates the fatty acid composition of the US diet. This fat blend was present at 10, 13.3, 16.7 or 20% by weight in the diet. For the fat type experiment, a 20% (w/w) fat diet containing either corn oil (exclusively) or lard (predominantly) was used. Mammary cancer prevention by CLA was evaluated using the rat dimethylbenz(alpha)anthracene model. The results indicated that the magnitude of tumor inhibition by 1% CLA was not influenced by the level or type of fat in the diet. It should be noted that these fat diets varied markedly in their content of linoleate. Fatty acid analysis showed that CLA was incorporated predominantly in mammary tissue neutral lipids, while the increase in CLA in mammary tissue phospholipids was minimal. Furthermore, there was no evidence that CLA supplementation perturbed the distribution of linoleate or other fatty acids in the phospholipid fraction. Collectively these carcinogenesis and biochemical data suggest that the cancer preventive activity of CLA is unlikely to be mediated by interference with the metabolic cascade involved in converting linoleic acid to eicosanoids. The hypothesis that CLA might act as an antioxidant was also examined. Treatment with CLA resulted in lower levels of mammary tissue malondialdehyde (an end product of lipid peroxidation), but failed to change the levels of 8-hydroxydeoxyguanosine (a marker of oxidatively damaged DNA). Thus while CLA may have some antioxidant function in vivo in suppressing lipid peroxidation, its anticarcinogenic activity cannot be accounted for by protecting the target cell DNA against oxidative damage. The finding that the inhibitory effect of CLA maximized at 1% (regardless of the availability of linoleate in the diet) could conceivably point to a limiting step in the capacity to metabolize CLA to some active product(s) which is essential for cancer prevention.



Dietary modifiers of carcinogenesis

Environmental Health Perspectives (USA) , 1995, 103/SUPPL. 8 (177-184)

Dietary components express a wide range of activities that can affect carcinogenesis. Naturally occurring substances in foods have been shown in laboratory experiments to serve as dietary antimutagens, either as bioantimutagens or as desmutagens. Dietary desmutagens may function as chemical inactivaters, enzymatic inducers, scavengers, or antioxidants. Dietary components may also act later in the carcinogenic process as tumor growth suppressors. Examples of dietary factors acting in each of these stages of carcinogenesis are presented, and potential anticarcinogens such as the carotenoids, tocopherols, phenolic compounds, glucosinolates, metal-binding proteins, phytoestrogens, and conjugated linoleic acid are discussed. individual foods typically contain multiple potential anticarcinogens. Many of these substances can influence carcinogenesis through more than one mechanism. Some substances exhibit both anticarcinogenic and carcinogenic activity in vitro, depending on conditions. Epidemiologic research indicates that high fruit and vegetable consumption is associated with lower cancer risk. Little research has focused on the effects of single substances or single foods in man. Realization of the potential of foodborne substances to reduce the human burden of cancer will only be achieved with better measurement of dietary

exposures and funding of muitidisciplinary research in this area commensurate with its importance.



Effects of C18 fatty acid isomers on DNA synthesis in hepatoma and breast cancer cells

Anticancer Research (Greece) , 1995, 15/5 B (2017-2021)

The influence of geometrical isomerism on the growth regulatory effects of 18 carbon unsaturated fatty acids on the incorporation of (3H)thymidine into DNA was studied in 7800NJ rat hepatoma and T47D human breast cancer cells. 9 cis, 12 cis linoleic acid was more inhibitory than the trans 9, trans 12 isomer (linolelaidic acid). The monounsaturated cis isomer. In contrast to published studies on the proliferation of breast cancer cells, we observed conditions in which linoleic acid was more inhibitory than conjugated linoleic acid for thymidine incorporation into DNA. Increasing the concentration of 38 mg/ml greatly diminished inhibitory effects and favored stimulatory effects on hepatoma and breast cancer cells. The results suggested that the growth inhibitory and stimulatory effects of C18 unsaturated fatty acids on cancer cells are influenced by geometrical isomerism and the ratio of the albumin to fatty acid concentrations



Effect of timing and duration of dietary conjugated linoleic acid on mammary cancer prevention

Nutrition and Cancer (USA) , 1995, 24/3 (241-247)

Conjugated linoleic acid (CLA) is a minor fatty acid found predominantly in the form of triglycerides in beef and dairy products. Previous work by Ip and co-workers showed that free fatty acid-CLA at less than or equal to1% in the diet is protective against mammary carcinogenesis in rats. The present study verified that the anticancer activities of free fatty acid-CLA and triglyceride-CLA are essentially identical. This is an important finding, because it rules out a nonspecific free fatty acid effect. In terms of practical implication, we can continue the in vivo research with the less-expensive free fatty acid- CLA without compromising the physiological relevance of the data. A primary objective of this report was to investigate how the timing and duration of CLA feeding might affect the development of mammary carcinogenesis in the methylnitrosourea (MNU) model. We found that exposure to 1% CLA during the early postweaning and pubertal period only (from 21 to 42 days of age) was sufficient to reduce subsequent tumorigenesis induced by a single dose of MNU given at 56 days of age. This period incidentally corresponds to a time of active morphological development of the mammary gland to the mature state. In contrast to the above observation, a continuous intake of CLA was required for maximal inhibition of tumorigenesis when CLA feeding was started after MNU administration, suggesting that some active metabolite(s) of CLA might be involved in suppressing the process of neoplastic promotion/progression.



The role of phenolics, conjugated linoleic acid, carnosine, and pyrroloquinoline quinone as nonessential dietary antioxidants

Nutrition Reviews (USA) , 1995, 53/3 (49-58)

Oxidative reactions have been implicated in the development of numerous diseases including atherosclerosis and cancer. Oxidation t in loss of membrane integrity and function, inactivation of enzymes, modification of lipoproteins, and chemical alteration of DNA. Active oxygen species, transition metals, reducing agents, and enzymes such as lipoxygenase are all involved in the catalysis of oxidative reactions. Since lipid oxidation catalysts and active oxygen species are ubiquitous to all biological systems and since lipid oxidation products can enter the body via oxidized foods, numerous endogenous antioxidant systems have been developed. Endogenous antioxidant systems include antioxidant enzymes, free radical scavengers, and metal chelators. The purpose of this review is to examine the potential of nonessential dietary components that inhibit oxidative reactions in foods and biological tissues.



Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atharosclerosis in hypercholasterolemic hamsters

Artery (USA) , 1997, 22/5 (266-277)

Conjugated linoleic acid is a collective term used to designate a mixture of positional and geometric isomers of linoleic acid in which the double bonds are conjugated. Unlike linoleic acid, there is a paucity of information regarding the effect of dietary conjugated linoleic acid on plasma lipoproteins and aortic atherosclerosis. Therefore, fifty hamsters were divided into five groups of ten and fed O (Control), 0.06 (LOW), 0.11 (MEDIUM), and 1.1(HIGH) en% conjugated linoleic acid or 1.1 en% linoleic acid. Blood samples were taken at 4, 8 and 11 weeks for plasma lipid analyses and for plasma tocopherol assay at sacrifice. Animals fed the conjugated linoleic acidcontaining diets collectively had significantly reduced levels of plasma total cholesterol, non-high density lipoprotein cholesterol, (combined very low and low density lipoprotein) and triglycerides with no effect on high density lipoprotein cholesterol, as compared to CONTROLs. Linoleic acid-fed animals relative to CONTROLs also had reduced plasma total cholesterol, non-high density lipoprotein cholesterol and triglycarides, but only the latter was statistically significant. Compared to the CONTROL group, plasma tocopherol/total cholesterol ratios determined from plasma pools for the LOW, MEDIUM and HIGH conjugated linoleic acid and linoleic acid groups were increased by 48%, 48%, 86% and 29%, respectively, suggesting a tocopherol-sparing effect, at least for the conjugated linoleic acid treatment. Morphomatric analysis of aortas revealed less early atherosclerosis in the conjugated linoleic acid and linoleic acid-fed hamsters compared to the CONTROL group.


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