Effect of mirex on the activities of various rat hepatic mixed-function oxidases

Abstract

Mirex (dodecachlorooctahydro-1,3,4-metheno-2H-cyclobuta[ cd ] pentalene) was orally administered to male and female rats at daily dosages of 5, t0, 25, and 50 mg/kg for 5 days and its effects on aniline hydroxylas, p-nitroanisole O-demethylase, ethyl morphine-N-demethylase, and UDP-glucmonyltransferase activities in the liver were studied. Liver-to-body weight ratios show significant increases at all of the doses tested, reaching maximum of 206 and 230 per cent of controls at a dose of 25 mg/kg for males and females, respectively. Metabolism of each of the substrates is altered by each dose of mirex fed. Aniline hydroxylase activity is decreased at all levels tested and the reduction is progressive with the dose. The Mirex content of rat liver microsomes is, by analysis, 9.69, 14.75, and 36.73 /lg per 0.2gram-equivalents of liver microsomes from male rats treated at 10, 25, and 50 mg/kg, respectively. Aniline hydroxylase activity is not affected by addition of up to 400 #g of mirex to the reaction mixtures, using liver preparations from untreated animals, p-Nitroanisote demethylation activity is induced to a maximum in animals treated at 5 mg/kg. Ethyl morphine demethylase is induced to a maximum by 10 mg/kg in male and 25 mg/kg in female rats. Higher doses manifest a reversal of p-nitroanisole-and ethyl morphine demethylase activities in both the sexes. Although the UDP-glucuronyl transferase specific activity is unaffected by mirex pretreatment, total activity in the liver increases to a maximum of 173 and t49 percent of controls at 25 mg/kg in males and females, respectively. Thus, it appears that chronic low doses of mirex seriously alter hepatic mixed-function oxidase systems of exposed animals, although mirex is not a substrate for any of these enzymes.

Atsdr Evaluation of Health Effects of Chemicals

“…Pregnant rats appear to be somewhat more sensitive to the lethal effect of mirex. Although a single oral dose of 25 mg/kg resulted in no mortality in nonpregnant females (Mehendale et al, 1973), 16-25% mortality in pregnant rats occurred at doses ranging from 6-10 mg/kg/day over a 10-11-day period during gestation (Khera et al, 1976;Chernoff et al, 1979b;Byrd et al, 1981). Similarly, a 32-36% mortality was observed in rat and mouse pups exposed through the milk during the first four days of lactation at these doses (Chernoff et al, 1979b).…”

“…Decreases greater than 10% in body weight or body weight gain have been observed in a number of mirex acute-duration studies (Mehendale et al, 1973;Khera et al, 1976;Chadwick et al, 1977;Villeneuve et al, 1977;Chernoff et al, 1979a,b;Byrd et al, 1981;Ritchie and Ho, 1982;Buelke-Sam et al, 1983;Fujimori et al, 1983;Jovanovich et al, 1987;Elgin et al, 1990), intermediate-duration studies (Davison et al, 1976;Chernoff et al, 1979b;Larson et al, 1979a;Chu et al, 1981b;Fujimori et al, 1983;Curtis and Hoyt, 1984;NTP, 1990), and chronic-duration studies (NTP, 1990).…”

“…When dosing occurs over several days, mortality is observed at substantially lower daily doses. Increased mortality in multiple-dose, acute-duration studies has been observed in female rats at doses as low as 50 mg/kg/day (Mehendale et al, 1973). Pregnant rats appear to be somewhat more sensitive to the lethal effect of mirex.…”

“…The adaptive effects observed are those generally produced by halogenated hydrocarbons; these include increase in liver weight or size (Gaines and Kimbrough, 1970;Mehendale et al, 1973;Abston and Yarbrough, 1976;Davison et al, 1976;Chadwick et al, 1977;Fulfs et al, 1977;Villeneuve et al, 1977;Robinson and Yarbrough, 1978a,c;Warren et al, 1978;Hewitt et al, 1979;Larson et al, 1979a;Pittz et al, 1979;Chu et al, 1980bChu et al, , 1981aMehendale, 1981b;Robacker et al, 1981;Yarbrough et al, 1981Yarbrough et al, , 1984Yarbrough et al, , 1986aYarbrough et al, ,b, 1992Ritchie and Ho, 1982;Chambers and Trevethan, 1983;Ervin and Yarbrough, 1983;Fujimori et al, 1983;Williams and Yarbrough, 1983;Curtis and Hoyt, 1984;Karl and Yarbrough, 1984;Jovanovich et al, 1987;Plaa et al, 1987;Purushotham et al, 1988;Wilson and Yarbrough, 1988;Elgin et al, 1990;Teo and Vore, 1991;Thottassery and Yarbrough, 1991 ). Other effects observed include hepatocellular hypertrophy (Gaines and Kimbrough, 1970;Davison et al, 1976;Fulfs et al, 1977;Ulland et al, 1977a;Yarbrough et al, 1981), cytopla...…”

Minimal Role of Enhanced Cell Proliferation in Skin Tumor Promotion by Mirex: A Nonphorbol Ester-Type Promoter

“…Although it has not been formally tested in an initiation-promotion protocol for liver carcinogenesis, mirex is not genotoxic in short-term, in vitro tests (9,10) and inhibits gap junctional communication (11), two characteristics of tumor promoters. Mirex induces proliferation of hepatocyte smooth endoplasmic reticulum (12,13) and mixed-function oxidase activities (14,15), as also occurs during the adaptive response of liver to other xenobiotic tumor promoters, such as phenobarbital (16). Consistent with the above hypothesis relating tumor promotion and cell proliferation, mirex stimulates liver growth, in part through hyperplasia (17) which is preceded by induction of ornithine decarboxylase activity (17,18) and stimulation of DNA synthesis (17,19).…”