Microsomal enzymes induction and

Urinary D-glucaric acid levels have been shown to be a sensitive indicator of microsomal enzyme induction in workers exposed to chlordecone (Guzelian 1985). However, other substances such as barbiturates, phenytoin, chlorbutanol, aminopyrine, phenylbutazone, and contraceptive steroids as well as other organochlorinated pesticides also cause microsomal enzyme induction and cause changes in urinary D-glucaric acid (Morgan and Roan 1974). 

Dannan GA, Sleight SD, Fraker PJ, et al. 1982. Liver microsomal enzyme induction and toxicity studies with 2,4,5,3, 4 -pentabromobiphenyl. Toxicol Appl Phannacol 64 187-203. 

In a subacute study, both male and female rats were fed diets containing octachlorostyrene at 0.5, 5.0, 50, and 500 mg kg for 28 days. Histological changes were observed in the liver and thyroid of rats exposed to doses equal to or greater than 5 mgkg. Hepatic microsomal enzyme induction and liver hypertrophy were observed in the two highest dose groups. At 500 mg kg there was an increase in... 

McClain RM (1989) The significance of hepatic microsomal enzyme induction and altered thyroid function in rats implications for thyroid gland neoplasia. Toxicol Pathol 17 294-306... 

As noted above, many of the AEDs induce hepatic microsomal enzyme systems and thus reduce the effectiveness of hormonal contraceptives. Women taking AEDs that may reduce the effectiveness of hormonal contraceptives should be encouraged to also use other forms of birth control. Due to induction or inhibition of sex hormone metabolism and changes in binding of hormones to sex hormone binding globulin, some AEDs may reduce fertility. For example, valproate has been associated with a drug-induced polycystic ovarian syndrome. Women who experience difficulties with fertility should seek the advice of health care professionals with expertise in fertility. 

Microsomal enzyme induction has been shown to be increased by both mirex and chlordecone in humans and/or experimental animals. Serum levels of chlordecone associated with enzyme induction in exposed workers were estimated to range from 100 to 500 pg/L (Guzelian 1985). 

McLean AEM. 1970. The effect of protein deficiency and microsomal enzyme induction by DDT and phenobarbitone on the acute toxicity of chloroform and a pyrrolizidine alkaloid, retrorsine. Br J Exp Pathol 51 317-321. 

C8. Coltart, J., Howard, M., and Chamberlain, D., Myocardial and skeletal muscle concentrations of digoxin on long-term therapy. Brit. Med. J. 11, 318-319 (1972). C9. Conney, A. H., Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev. 19, 317-366 (1967). 

There are many factors in the environment, which may influence drug disposition, metabolism, and toxicity to a greater or lesser extent. However, as the influence of certain foreign compounds, both drugs and those in the environment, on microsomal enzymes has been well studied, this will constitute a separate section "Enzyme induction and Inhibition". 

Shen ES, Guengerich FP, Olson JR. 1989. Biphasic response for hepatic microsomal enzyme induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J mice. Biochem Pharmacol... 

Particularly likely to occur when a tricyclic drug, a phenothiazine, and a antiparkinsonian drug are prescribed concurrently Tricyclic drugs can interfere with the metabolism of oral anticoagulants Convulsive threshold lowered Hepatic microsomal enzyme induction Hypertension should be controlled with diuretics, p-blockers, or vasodilators before treatment of depression... 

Microsomal enzyme induction may shorten the half-life of rifampin and decrease drug concentrations of concurrently administered... 

Chlorpromazine is strongly bound to protein, crosses blood-brain barrier, and concentrates in the brain against plasma gradient. More than 90% of the drug in plasma is bound to proteins, is metabolized in the liver, and is excreted in both urine and feces. There is some evidence that chlorpromazine can cause hepatic microsomal enzyme induction, which indicates that it may accelerate its own metabolism. 

Enzymes of the hepatic microsomal system can be induced or inhibited. Enzyme induction and inhibition have greatest significance for drugs with low to moderate hepatic extraction fractions. 

Microsomal enzyme induction leads to an increase in the activity of enzymes present, most commonly through increases in the mass quantity of the oxidizing enzymes. The many isoenzymes of cytochrome P450 are affected variably by different enzyme-inducing drugs. For example, phenobar-bital and theophylline and polycycUc hydrocarbons induce enzyme activity differently. Two classical and clmicaUy relevant enzyme inducers can be contrasted. 

Hepatic Effects. The hepatotoxic potential of PCB mixtures is well-documented in animals by oral and other routes of exposure. The spectrum of possible hepatic effects in animals is broad and includes microsomal enzyme induction, liver enlargement, increased serum levels of liver enzymes and lipids, and histopathologic alterations that progress to fatty and necrotic lesions and tumors. The findings of human studies, however, are not as obvious. Many of the human studies involving worker and other populations with high body burdens of PCBs report associations between PCBs and hepatic indices such as liver... 

In humans, clinical studies of PCB workers reported associations between increased serum levels of liver-related enzymes, lipids, and cholesterol and serum PCBs. Studies of people exposed to PCBs by ingestion of contaminated fish in Triana, Alabama or contaminated rice oil in the Yusho or Yu-Cheng incidents have reported increases in serum levels of some liver enzymes characteristic of microsomal enzyme induction or liver damage, but these effects cannot be attributed solely to PCBs due to the mixed chemical nature of the contaminated fish and heated rice oil exposures. Serum cholesterol, but not triglycerides, was increased in consumers of contaminated fish, whereas increased serum triglycerides, but not cholesterol, were associated with Yusho and Yu-Cheng exposure. 

Aroclor 1254 for durations as short as 1-3 days (Bruckner et al. 1977) no other hepatic end points were evaluated in this study. Relative liver weight and serum total cholesterol were increased in rats that were fed estimated doses of i mg/kg/day Aroclor 1254 for 4 days, but not 0.5 mg/kg/day (Carter 1984, 1985) histology was not evaluated. Acute-duration studies evaluating hepatic effects of PCBs other than microsomal enzyme induction at doses lower than those in the Carter (1984, 1985) studies were not located. Effects in rats exposed to higher doses of PCBs in acute-duration studies included increased liver weight, decreased Uver glucose 6-phosphatase, and/or decreased serum cholesterol at... 

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