Liver microsomal enzyme inducers

Liver microsomal enzyme inducers that are lipid soluble at the physiologic pH can be classified into two general groups. Some, such as phenobarbital, tend to stimulate all enzymes others, such as 3-methylcholanthrene, tend to be selective. The administration of phenobarbital increases the amounts of NADPH-cytochrome C reductase and P-450, and the rate of P-450 reduction. In contrast, the administration of 3-methylcholanthrene increases the amount of P-450 but neither the activity of NADPH-cytochrome C reductase nor the rate of P-450 reduction. 

Glutethimide has strong sedative activity and is an inducer of the liver microsomal enzymes. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Hepatic Effects. Exposure to 2,3,7,8-TCDD induces liver microsomal enzymes in both humans and animals, regardless of the route or duration of exposure. Increased urinary -glucaric acid (UGA) excretion, an indirect index of enzyme induction, was found in children with chloracne living in the Seveso area following the 1976 industrial accident (Ideo et al. 1982). Biochemical changes (increased... 

Cheng X, Maher J, Dieter MZ, et al. Regulation of mouse organic anion-transporting polypeptides (Oatps) in liver by prototypical microsomal enzyme inducers that activate distinct transcription factor pathways. Drug Metab Dispos 2005 33 1276-1282. 

Visser TJ, Kaptein E, van Toor H, et al. Glucuronidation of thyroid hormone in rat liver effects of in vivo treatment with microsomal enzyme inducers and in vitro assay conditions. Endocrinology 1993 133 2177-2186. 

Drugs that induce liver microsomal enzymes, such as phenobarbital, phenytoin, carbamazepine, rifampicin, and isoniazid, can make paracetamol poisoning more severe (104,105). In patients taking such drugs the serum paracetamol concentration should be doubled before consulting the usual treatment nomogram. 

There are metabolic differences between the sexes. Many barbiturates induce more prolonged sleep in female rats than in males. The shorter duration of action of hexobarbital in male rats is related to the higher activity of the liver microsomal enzymes stimulated by testosterone to hydroxylate this chemical. This higher activity can be reduced by castration or pretreatment with estrogen (female hormone). 

Conney AH, Gillette JR, Inscoe JK, Trams ER, Posner HS. 1959. Induced synthesis of liver microsomal enzymes which metabolize foreign compounds. Science 130 1478-79... 

The hepatic mechanistic studies in the rat were thus of great value to show that the probable mechanism exists for PBO to cause such thyroid effects in the ral as a consequence of its potent microsomal enzyme-inducing activity. The fact that PBO showed a closely comparable profile to the archetypal inducer phe nobar bit one, which also induces increased thyroid activity, serves only to reinforce the likelihood that this is a classic secondary mechanism. The primary effect of both xcnobiotics is inextricably linked to their biological property of liver enzyme induction. This perturbation in turn leads to remote secondary effects on the thyroid. By recognizing and understanding this mechanism it may be appreciated that the levels of PBO to which humans might be exposed are more than 1000 times below the threshold for any effect in the liver. In the absence of any primary hepatic effect there can be no risk (o humans of any secondary (thyroidal) effect, to which they are in any case significantly less sensitive to than the rat. 

McClain, R.M. ( 990). Mouse liver tumours and microsomal enzyme inducing drugs. Experimental and Clinical perspectives with phenobarhital. In Mouse Liver Carcinogenesis. Mechanisms ond Species Comparison, pp, 345-365. 

Studies of 1,1,1 -trichloroethane s effects on liver enzyme activity are inconclusive. Acute inhalation of high concentrations induced the activity of liver microsomal enzymes (e.g., cytochrome P- 450, NADPH cytochrome c reductase) in rats and mice (Fuller et al. 1970 Lal and Shah 1970). 

Tatematsu M, Nakanishi K, Murasaki G, et al. 1979. Enhancing effect of inducers of liver microsomal enzymes on induction of hyperplastic liver nodules by N-2-fluorenylacetamide in rats. J Natl Cancer Inst 63 1411-1416. 

Shelby, M. K. and Klaassen, C. D. (2006) Induction of rat UDP-glucuronosyltransferases in liver and duodenum by microsomal enzyme inducers that activate various transcriptional pathways. Drug Metab. Dispos. 34, 1772-1778. 

Parkinson, A., Mudra, D. R., Johnson, C., Dwyer, A., and Carroll, K. M. (2004) The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol. Appl. Pharmacol. 199, 193-209. 

Poli, G., K. Cheeseman, T.F. Slater, and M.U. Danzani (1981). The role of lipid peroxidation in CCI,-induced damage to liver microsomal enzymes Comparative studies in vitro using microsomes and isolated liver cells. Chem. Biol. Interact. 37, 13-24. 

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