Microsomal enzyme inducers

Both mirex and chlordecone are microsomal enzyme inducers, and as such enhance the metabolism of compounds oxidized or reduced by the mixed function oxygenase system. For... 

D.R. Johnson and C.D. Klaassen. Regulation of rat multidrag resistance protein 2 by classes of prototypical microsomal enzyme inducers that activate distinct transcription pathways. Toxicol Sci. 67 182-189 (2002). 

Madan A, Graham RA, CarroU KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P, Jr., Koch P, Antonian L, Wagner G, Yu L, Parkinson A (2003) Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos31(4) 421 31... 

Abdelsalam , Ford EJ. 1986. Effect of pretreatment with hepatic microsomal enzyme inducers on the toxicity of diazinon in calves. Res Vet Sci 41(3) 336-339. 

Two examples of toxicity, where the target is known, are carbon monoxide, which interacts specifically with hemoglobin, and cyanide, which interacts specifically with the enzyme cytochrome a3 of the electron transport chain (see chap. 7). The toxic effects of these two compounds are a direct result of these interactions and, it is assumed, depend on the number of molecules of the toxic compound bound to the receptors. However, the final toxic effects involve cellular damage and death and also depend on other factors. Other examples where specific receptors are known to be involved in the mediation of toxic effects are microsomal enzyme inducers, organophosphorus compounds, and peroxisomal proliferators (see chaps. 5-7). 

It is clear that the effects of induction or inhibition of the metabolism will be complex because of the large number of possible metabolic pathways through which benzofalpyrene may be metabolized. For instance, the microsomal enzyme inducer 5,6-benzoflavone inhibits the carcinogenicity of benzofalpyrene in mouse lung and skin, whereas inhibitors such as SKF 525A may increase the tumor production from certain polycyclic hydrocarbons. 

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. 

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. 

Hurwitz A. 1972. Effects of microsomal enzyme inducers on animals poisoned with hepatotoxins. Toxicol Appl Pharmacol 22 339-346. 

Carbamazepine is a hepatic microsomal enzyme inducer and therefore will lower the serum concentration of a wide variety of drugs given concurrently. These include the antiepileptic drugs phenytoin, primidone, valproate, ethosuximide and clonazepam. In addition, carbamazepine can compromise the therapeutic effects of oral contraceptives, oral anticoagulants, beta-blockers, haloperidol and theophylline. 

Rausch-Derra LC, Hartley DP, Meier PJ, et al. Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2. Hepatology 2001 33 1469-1478. 

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. 

Many CYP3A substrates are also subject to efflux transport by P-gp at the intestinal mucosa (88-90). As discussed above, P-gp is inducible via activation of nuclear orphan receptors by the same inducers of CYP enzymes (91). Accordingly, for those drugs which are substrates of both CYP and P-gp, reduction in intestinal availability following treatment with known microsomal enzyme inducers could reflect the joint effects of increased mucosal metabolism and apical efflux. 

Madan A, Graham RA, Carroll KM, et al. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos 2003 31 421—431. 

Vansell NR, Klaassen CD (2001) Increased biliary excretion of thyroxine by microsomal enzyme inducers. Toxicol Appl Pharmacol 176 187-194... 

Mirex is a potent microsomal enzyme inducer. Mirex may inhibit Na,K-ATPase and interfere with energy production and utilization. Mirex is also a non-phorbol ester tumor promoter. 

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. 

Hood A, Klaassen CD (2000) Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyronine (T(3)) glucuronidation. Toxicol Sci 55(l) 78-84... 

Alnouti Y, Klaassen CD (2008) Tissue distribution, ontogeny, and regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by prototypical microsomal enzyme inducers in... 

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