Hepatic microsomal enzymes

Intestinal absorption of digoxin is less complete compared to digitoxin. In order to improve absorption, acetylated- and methylated-digoxin derivates were developed. Digitoxin is metabolised in hepatic microsomal enzymes and can be cleared independently from renal function. The therapeutical serum level of digoxin is 0.5-2.0 ng/ml and 10-35 ng/ml of digitoxin. Steady state plateau of therapeutic plasma concentrations is reached after 4-5 half-life-times using standard daily doses [5]. 

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). 

Cimetidine, an H2 antagonist used therapeutically in patients with ulcers, inhibits activity of hepatic microsomal enzymes. When rats or mice were pretreated with cimetidine, dose-related lethality of methyl parathion was reduced, and cholinergic signs of toxicity were delayed. Simultaneous administration with methyl parathion did not reduce toxicity (Joshi and Thornburg 1986). 

Walker, C.H. (1980). Species variations in some hepatic microsomal enzymes that metabolise xenobiotics. Progress in Drug Metabolism 5, 118-164. 

Table VI lists several drugs Inducing hepatic microsomal enzymes (5). These enzymes can metabolize the drug as well as other substrates. Barbiturates, grlseofulvln, and glutethlmlde Induce enzymes which metabolize coumarln and phenlndlone derivatives and thus reduce their anticoagulant activity. Dlphenylhydantoln and phenylbutazone stimulate cortisol hydroxylase activity and Increase the urinary excretion of B-hydroxy cortisol and decrease the concentration of cortisol In the plasma.

Carbamazepine is a potent inducer of hepatic microsomal enzymes. Not only does it increase the rate of metabolism for many other drugs, it increases the rate of its own metabolism. Hepatic enzymes become maximally induced over several weeks, necessitating a small initial dose of carbamazepine that... 

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. 

Some OC pesticides can induce the hepatic microsomal enzyme system (Kay, 1970). Tests measuring functions related to these enzymes, such as f.i. D-glucaric acid and 6-b-hydroxicortisol excretion in urine, can be applied to monitor occupational OC exposure. 

Strong evidence indicates that endrin increases the activity of hepatic microsomal enzymes (Klaasen et al. 1986). Drugs which are strong inducers of microsomal enzymes may increase the metabolic elimination of endrin. 

Hunter J, Maxwell JD, Stewart DA, et al. 1972. Increased hepatic microsomal enzyme activity from occupational exposure to certain organochlorine pesticides. Nature 237 399-401. 

DuBois KP, Kinoshita FK. 1968. Influence of induction of hepatic microsomal enzymes by phenobarbital on toxicity of organic phosphate insecticides. Proc Soc Exp Biol Med 129 699-702. 

Induction of Hepatic Microsomal Enzymes in Rainbow Trout... 

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...

Statham, C.N., Elcombe, C.R., Szyjka, S.P. and Lech, J.J. Effect of polycyclic aromatic hydrocarbons on hepatic microsomal enzymes and disposition of methylnaphthalene in rainbow trout in vivo. Xenobiotica. (1978) j3 65-71. 

T. Horie, T. Ohno, K. Kinoshita, H. Kitagawa, M. Kitada, Studies of Metabobsm of Tri-pamide, a New Antihypertensive Agent. II. Metabobsm by the Hepatic Microsomal Enzymes , Xenobiotica 1981, 11, 693-699. 

Walter Reed-Wistar and Charles River male adult rats were exposed to oral doses of turpentine or to turpentine vapors, which consisted of a- and p-pinene. These exposures were followed by oral administration of heptachlor epoxide or of one of three pesticides, paraoxon, heptachlor, or parathion, or by an intraperitoneal injection of hexobarbital. The studies revealed that pretreatment with turpentine reduced hexobarbital sleeping time, reduced the parathion LDso, and increased the heptachlor LDso. The paraoxon and heptachlor epoxide LOo values were unchanged. a-Pinene and P-pinene vaporized from turpentine had no effect on either hexobarbital sleeping time or parathion, paraoxon, or heptachlor epoxide mortality but did increase the heptachlor LDso (Sperling et al. 1972). The authors speculated that increases in hepatic microsomal enzyme activity are responsible for these differences. 

Dichlorobenzidine is an effective inducer of its own metabolic activation (Iba 1987a). The enhancement of 3,3 -dichlorobenzidine mutagenesis has been associated with the induction of cytochrome P-450d (Iba and Thomas 1988), and may result in the elevation of its carcinogenicity. In other animal studies, 3,3 -dichlorobenzidine was also shown to be a potent inducer of hepatic microsomal enzymic activities mediated by cytochrome-P-448 and P-450 (Iba and Sikka 1983 Iba and Thomas 1988). Consequently, it has been suggested that the hepatocarcinogenicity of 3,3 -dichlorobenzidine may be due, at least in part, to the induction of hepatic cytochrome P-488 and DNA-adduction. 

In experimental animals, prolonged exposure to dietary levels exceeding 3-5mg/kg resulted in the induction of hepatic microsomal enzymes and, at a later stage, liver hypertrophy with histologic changes. 

Large oral doses of DDT in rats caused focal and centrilobular necrosis of the liver. However, in clinical evaluation and laboratory studies of 31 workers exposed to equivalent oral intakes of 3.6-18 mg daily for an average of 21 years, there was no evidence of hepatotoxicity an observed increase in activity of hepatic microsomal enzymes was not accompanied by clinical evidence of detriment to general health. ... 

There was no effect on hexobarbital-induced sleep times in rats exposed continuously to 225 ppm 2-hexanone (purity not stated) for 7 days (Couri et al. 1977). Thus, 2-hexanone exposure under these conditions does not seem to affect the hepatic microsomal enzyme activities associated with this response. No histopathological effects were seen in the livers of rats exposed to 50 ppm 2-hexanone (purity not stated) for 6 months (Duckett et al. 1979). However, no additional data on potential hepatic effects were found. 

The dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios, or being given to patients with hepatic impairment, may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. 

Metabolism/Excretion- Nartar n is metabolized by hepatic microsomal enzymes and are excreted primarily in the urine and feces as inactive metabolites. 

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