Microsomal enzymes, control

Jefcoate, and H.C. Pitot. Chatacteristics of microsomal enzyme controls in primary cultures of rat hepatocytes. Arch. Biochem. Biophys. 192 61-72,... 

Collinge, D. and M.A. Hughes (1984). Evidence that linamarin and lotaustralin, the two cyanogenie glucosides of Trifolium repens L., are synthesized by a single set of microsomal enzymes controlled by the Ac/ac locus. Plant Sci. Lett. 34, 119-125. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

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. 

In this study, P-450-related enzyme activities (benzphetamine N-demethylase, 7-ethoxycoumarin O-deethylase) were also measured in liver homogenates (prepared 24 hours after the last treatment) from rats treated orally with MEK for 1-7 days and compared to the activity obtained with phenobarbital treatment (80 mg/kg intraperitoneally for 3 days) (Robertson et al. 1989). Total cytochrome P-450 was also measured. No consistent change was noted in benzphetamine N-demethylase activity as the result of MEK treatment, while 7-ethoxycoumarin O-deethylase was over 3 times higher than controls and comparable to phenobarbital induction. Total P-450 levels were increased to approximately 150-200% of controls with MEK and to 570% of control by phenobarbital. The authors concluded that the potentiating effects of MEK on the neurotoxicity of -hexane appear to arise, at least in part, from the activating effects of MEK on selected microsomal enzymes responsible for -hexane activation. 

Figure 1. Effect of potential inducing agents on certain hepatic microsomal enzymes of the rainbow trout. Animals were infected intraperitoneally with either phenobarbital (65 mg/kg) 3-methylcholanthrene (20 mg/kg) 2,3-benzanthracene (10 mg/kg) or /3-naphthoflavone (100 mg/kg). The animals were sacrified and hepatic microsome prepared 48 hr after infection. Each bar is the mean SE (n = 3-5) ( ), induced activity (T) significantly different from control (C) activity...

The marine environment acts as a sink for a large proportion of polyaromatic hydrocarbons (PAH) and these compounds have become a major area of interest in aquatic toxicology. Mixed function oxidases (MFO) are a class of microsomal enzymes involved in oxidative transformation, the primary biochemical process in hydrocarbon detoxification as well as mutagen-carcinogen activation (1,2). The reactions carried out by these enzymes are mediated by multiple forms of cytochrome P-450 which controls the substrate specificity of the system (3). One class of MFO, the aromatic hydrocarbon hydroxylases (AHH), has received considerable attention in relation to their role in hydrocarbon hydroxylation. AHH are found in various species of fish (4) and although limited data is available it appears that these enzymes may be present in a variety of aquatic animals (5,6,7,8). 

The mechanism of toxification of isoniazid was investigated in rats pretreated with inducers or inhibitors of microsomal enzymes or an inhibitor of acylamidases. In animals pretreated with the acylamidase inhibitor bis(4-nitrophenyl) phosphate, isoniazid and acetylisoniazid produced less liver necrosis than in control animals. The treatment had no effect on the necrosis due to acetylhydrazine [173], In animals pretreated with inducers of microsomal cytochrome P450 such as phenobarbital, acetylisoniazid, and acetylhydrazine caused markedly increased necrosis, while pretreatment with cytochrome P450 inhibitors decreased necrosis. In contrast, the toxicity of isoniazid and hydrazine was not modified by phenobarbital pretreatment. From these observations, Trimbell et al. [173] concluded that the hydrolysis of acetylisoniazid is a prerequisite for hepatotoxicity, and that microsomal enzymes transform acetylhydrazine, the product of hydrolysis, to a toxic species. 

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... 

Fig. 12. Paraffin sections of rat liver, periodic acid Schiff stain X22. A, normal liver of control animal killed 24 h after injection of 1 ml of seasame oil i.p. B, extensive centrolobular necrosis of parenchymal cells in rat killed 24 h after administration of high dose of bromobenzene (0.2 ml i.p.). C, Liver 24 h after lower dose of bromobenzene (0.03 ml i.p.). The centrolobular areas exhibit some small patches of round cell infiltration and decreased glycogen staining in the cytoplasm after hepatocytes but little necrosis. D, Extensive centrolobular necrosis after administration of the same low dose of bromobenzene (0.03 ml i.p.) to a rat treated with pheno-barbital (20 mg/kg) for 3 days in order to induce hepatic microsomal enzymes. After Brodie et al...

During bile acid biosynthesis, modifications to the cyclopentanophen-anthrene (steroid) nucleus are thought to precede the oxidation and cleavage of the cholesterol side chain. The first and rate-controlling step in bile acid synthesis is the 7o-hydroxylation of cholesterol (I) to form 7a-hydroxy-choles-terol (II) (Fig. 3). This step is catalyzed by cholesterol 7a-monooxygenase (cholesterol 7a-hydroxylase) (EC 1.14.13.17), a microsomal enzyme (M37). Further metabolism of 7a-hydroxy-cholesterol involves oxidation of the 3p-hydroxyl group and isomerization of the double bond from C-5,6 to C-4,5,... 

In sheep pretreated with DDT, a dose of 63.2 mg carbon disulfide/kg/day was reported to cause hepatic lesions accompanied by microsomal enzyme suppression and increases in total liver water and electrolytes (Wilkie et al. 1985). This study is of limited value because of its lack of controls to eliminate or account for possible synergistic effects of carbon disulfide and DDT. 

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