Co-mutagenic activity of phenoxyherbicides MCPA- and MCPB-ethylester in the Ames assay.

The effects of ethyl 4-chloro-2-methylphenoxyacetate (MCPA) on the cholesterol levels in the liver, serum and gallbladder bile, the composition of both biliary lipids and bile acids, and the hepatic enzyme activities relating to the bile acid formation were investigated in male golden hamsters. MCPA was administered orally to the animals at the doses of 200, 500 and 1,000 mg/kg/day for 2 weeks. Clofibrate (500 mg/kg/day) was also tested for comparison, because of its similarity to MCPA in chemical structure and pharmacological actions. Body weight gain was slightly decreased, but liver to body weight ratio was increased in the MCPA groups of 500 and 1,000 mg/kg and also in the clofibrate group. In these groups, the cholesterol level in the liver was decreased but that in bile was increased. The composition of biliary bile acids was also changed in both the MCPA groups (500 and 1,000 mg/kg) and the clofibrate group, but in a different manner ; the levels and proportions of secondary bile acids were increased in the MCPA groups, while those of cholic acid and deoxycholic acid were decreased in the clofibrate group. These results indicate that MCPA and clofibrate may affect cholesterol catabolism differently, although these two compounds contain the same chlorinated phenoxy acid moiety. The increased level of cholesterol in bile might lead to the formation of cholesterol gallstone, which is frequently found in patients with gallbladder cancer. It is inferred that exposure to MCPA could be a risk factor for gallbladder cancer, which was initiated with some chemical carcinogens, because it increased the levels and proportions of both cholesterol and secondary bile acids in bile.ethyl 4-chloro-2-methylphenoxyacetate ; bile composition ; golden hamster ; gallbladder cancer ; clofibrateThe mortality rates of biliary tract cancers (BTCs), especially gallbladder and the extrahepatic bile duct cancers, are high in Japan compared to those in other countries in the world (Yamamoto et al. 1988). Moreover, the death rate of BTCs in Niigata Prefecture is the highest in Japan (Tominaga et al. 1979). Yamamoto et al. (1986) reported that the prefectures with high BTC mortality are located in the areas where rice production is high. They also pointed out that the

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confidence: 99%

Effects of Ethyl 4-Chloro-2-Methylphenoxyacetate on Bile Composition in Golden Hamsters.

Inomata

1992

“…Some investigators have found evidence suggesting that these compounds are related to an increased incidence of soft tissue sarcomas in epidemiological studies (Hardell and Sandstrom 1979;Moses and Selikoff 1981). MCPA is not mutagenic (Moriya et al 1983;IARC 1983), but it amplifies growth inhibition originally induced by mitomycin C (Yamamoto et al 1988b), and enhances the mutagenicity of 2-aminoanthracene (Shibuya et al 1990). A phenoxyacid herbicide, 2, 4-dichlorophenoxyacetic acid (2, 4-D), is not mutagenic in the Ames test, but may be carcinogenic in experimental animals (Reuber 1983).…”

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confidence: 99%

Effects of MCPA and Other Phenoxyacid Compounds on Hepatic Xenobiotic Metabolism in Rats.

Inomata¹,

Yoshida

Aoki

et al. 1991

Self Cite

The effects of ethyl 4-chloro-2-methylphenoxyacetate (MCPA) and other phenoxyacid compounds on hepatic xenobiotic metabolizing enzymes were studied in male rats. These compounds were administered orally 200 mg/kg/day to the rats for 2 weeks. Both MCPA and clofibrate increased the hepatic level of cytochrome P-450. In the MCPA-treated group, the activities of aniline hydroxylase and 7-ethoxycoumarin 0-deethylase increased by 15% and 1.5-fold, respectively. The free acid form of MCPA increased these activities more potently than MCPA. Both MCPA and its free acid did not change the activity of aminopyrine N-demethylase. A marked increase in the activity of aniline hydroxylase was noted in the 2, 4-dichlorophenoxyacetic acid-treated group, whereas the aminopyrine N-demethylase activity significantly decreased in the same group. Clofibrate also increased the activities of hepatic microsomal cytochrome P-450-mediated oxidation tested, but to a lesser extent when compared with the effects of MCPA. These results indicate that MCPA may have a potent effect on the hepatic metabolizing enzymes in rats, and also that the induction of xenobiotic metabolizing enzymes may change when the chemical moiety of phenoxyacid compounds is modified.ethyl 4-chloro-2-methylphenoxyacetate ; phenoxyacid herbicides ; hepatic xenobiotic metabolism ; rat ; bile acidThe death rate for biliary tract cancer (BTC) in Japan is comparatively high in the world (Yamamoto et al. 1988a). High BTC mortality rates are concentrated in areas where rice is grown in Japan, with Niigata prefecture having the highest of all. Yamamoto et al. (1986) analyzed the ecological correlation between agricultural chemicals and standardized mortality ratios (SMRs) for BTC deaths in Japan.They found that the use of ethyl 4-chloro-2-methylphenoxyacetate (MCPA), a phenoxyacid herbicide, is significantly correlated to SMRs.

“…Yamamoto et al analyzed the statistical correlation between agricultural chemicals and standardized mortality ratios (SMRs) for death from BTC and found that the use of ethyl 4-chloro-2-methylphenoxyacetate (MCPA), a phenoxyacid herbicide, was significantly correlated with the SMRs. MCPA itself is not mutagenic (Moriya et al 1983) but has co-mutagenic action (Yamamoto et al 1988 ;Shibuya et al 1990). MCPA has not only the inductive effect on hepatic xenobiotic metabolizing enzymes ) but also the proliferative action of hepatic peroxisome.…”

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confidence: 99%

Effects of Ethyl 4-chloro-2-methylphenoxyacetate on Hepatic Peroxisomal Enzymes in Rats.

Inomata

Yoshida

Aoki

et al. 1991

Self Cite

Effects of ethyl 4-chloro-2-methylphenoxyacetate (MCPA) and clofibrate on the activities of hepatic lipid metabolizing enzymes in the peroxisomal fraction from rat liver were studied, and these drugs were found to potentiate the peroxisomal enzyme activity. The results imply that MCPA affects lipid metabolism as well as clofibrate. MCPA ; peroxisomal enzyme ; rat High death rate for biliary tract cancer (BTC) is concentrated in areas where rice production is high in Japan (Yamamoto et al. 1986). Yamamoto et al. analyzed the statistical correlation between agricultural chemicals and standardized mortality ratios (SMRs) for death from BTC and found that the use of ethyl 4-chloro-2-methylphenoxyacetate (MCPA), a phenoxyacid herbicide, was significantly correlated with the SMRs. MCPA itself is not mutagenic (Moriya et al. 1983) but has co-mutagenic action (Yamamoto et al. 1988 ;Shibuya et al. 1990). MCPA has not only the inductive effect on hepatic xenobiotic metabolizing enzymes ) but also the proliferative action of hepatic peroxisome. Both the microsomal drug metabolizing system and peroxisomal fatty acid /3-oxidation are know to be concerned with the biotransformation of cholesterol into bile acids. Abnormal bile composition and metabolism may be important factors in the pathogenesis of BTC. It is possible that the change of lipid metabolism in the liver affects bile formation. These considerations led us to investigate the effect of MCPA on hepatic lipid metabolism. In this study, we examined the effect of MCPA on the activities of lipid metabolizing enzymes in the hepatic peroxisomas in rats for comparison with clofibrate (ethyl 2-(p-chlorophenoxy) isobutyrate). Clofibrate, a hypolipidemic drug, has not only the proliferative action of peroxisomes ) but also the same chlorinated phenoxyacid moiety as MCPA.MCPA was dissolved in olive oil and administered orally to Sprague Dawley-strain male rats (173-196 g) for 2 weeks at 100, 200 or 300 mg/kg/day. Clofibrate was also dissolved in the same vehicle and administered at the doses of 200 or 300 mg/kg/day in the same way.The effects of MCPA and clofibrate on body weight, liver weight, and peroxisomal