Microsomal enzyme system

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

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. 

Alternatively, acrylonitrile is metabolized to 2-cyanoethylene oxide by the microsomal enzyme system. 2-Cyanoethylene oxide can react directly with tissue macromolecules or it can be further metabolized to oxidation products that release cyanide. Cyanide is converted to thiocyanate and excreted in the urine. 2-Cyanoethylene oxide is also conjugated with glutathione and metabolized to 2- hydroxyethylmercapturic acid which is excreted in the urine. 

Figure 1. The major pathways in the metabolism of BaP to BaP epoxides, dihydrodiol, and 7,8-dihydrodiol-9,10-epoxides. The absolute configurations are as shown. The position of trans-addition of water is shown by an arrow. The optical purity of the 4,5-epoxide formed in BaP metabolism is dependent on the cytochrome P-450 isozymes present in the microsomal enzyme system. EH epoxide hydrolase.

Testosterone represents the immediate precursor of the oestrogens, the conversion being catalysed by the aromatase complex, i.e. a microsomal enzyme system. The biological actions of oestrogens may be summarized as ... 

DU, L., LYKKESFELDT, J, OLSEN, C.E., HALKIER, B.A., Involvement of cytochrome P450 in oxime production in glucosinolate biosynthesis as demonstrated by an in vitro microsomal enzyme system isolated from jasmonic acid-induced seedlings oiSinapis alba L, Proc. Natl. Acad. Sci. USA, 1995, 92, 12505-12509. 

The electron transfer system has not been studied in detail in fish, but the metabolism of compounds such as biphenyl (37), benzo(a)pyrene (21) and 2,5-diphenyloxazole (38) by fish liver microsomes has been shown to require oxygen and NADPH generating system. The metabolism of BP (21), 2,5-diphenyloxazole (Ahokas, unpublished observation) and aldrin (27.) by fish liver microsomal enzyme system is inhibited strongly by carbon monoxide. This information and the fact that cytochrome P-1+50, as well as NADPH cytochrome c reductase system are present in fish, suggest strongly that fish have a cytochrome P-1+50 mediated monooxygenase system which is very similar to that described in mammals. 

Mannering, G.J. Microsomal enzyme systems which catalyze drug metabolism. In La Du, B.N., Mandel, H.G. and Way, E.L. (Eds.) Fundamentals of Drug Metabolism and Disposition. Baltimore, Williams.(1971). 

A biological difference that could increase susceptibility of fetuses and premature or perinatal infants to 1,2-dibromoethane toxicity is developmental immaturity of the P-450 (microsomal enzyme) system. Biotransformation of xenobiotics occurs predominantly by glutathione conjugation (Benet and Sheiner 1985 Sipes and Gandolfi 1986). This pathway is known to generate a number of toxic intermediate metabolites of 1,2-dibromoethane. In addition, fetal mice have selective binding of... 

Sorghum microsomal enzyme system Production of 25 from tyrosine, isomerization of oxime 25 to 26, and its conversion to hydroxymandelonitrile 106, 117... 

Sorghum microsomal enzyme system l-Nitro-2-(p-hydroxyphenyl)ethane is a precursor of oxime 25 = 0.05 mM and Vmax = 14 nmol mg h 106... 

West. S.B. and Lu, A.Y. (1972) Reconstituted liver microsomal enzyme system that hydroxylates drugs, other foreign compounds and endogenous substrates. V. Competition between cytochromes P-450 and P-448 for reductase in 3,4-benzpyrene hydro-xylation. Archives of Biochemistry and Biophysics, 153, 298-303. 

Pharmacokinetics Well absorbed from the gastrointestinal (Gl) tract. Protein binding 52%-57%. Crossesblood-brain barrier. Widely distributed. Metabolized in liverby microsomal enzyme system to inactive and active metabolites. Primarily excreted in urine. Not removed by hemodialysis. Half-life 15-40 hr. 

Certain drugs induce the hepatic microsomal enzyme system i.e. enzyme induction, which decreases the effectiveness of other drugs, for example, if phenobarbital is suddenly discontinued without lowering the dosage of coumarin, severe hemorrhage can occur. 

Although it is difficult to assess whether induction or inhibition of hepatic microsomal enzyme systems will have any practical bearing on the health of humans, such hazards cannot be excluded. 

Alcohol and aldehyde oxidation. Although a microsomal enzyme system has been demonstrated, which oxidizes ethanol (see above), probably the more important enzyme in vivo is alcohol dehydrogenase, which is a cytosolic enzyme (soluble fraction) and is found in the liver and also in the kidney and the lung. 

It is postulated that this ultimate carcinogen reacts covalently with nucleic acids, producing nucleic acid adducts. It has been demonstrated that benzo[a]pyrene reacts covalently with nucleic acids in vitro, provided that the microsomal enzyme systems necessary for activation are present, and also in whole cell systems. The 7,8-dihydrodiol metabolite of benzo [alpyrene binds more extensively to DNA after microsomal enzyme activation than does benzo [alpyrene or other benzolalpyrene metabolites, and the nucleoside adducts formed from the 7,8-dihydrodiol of benzolalpyrene are similar to those obtained from cells in culture exposed to benzolalpyrene itself. Furthermore, the synthetic 7,8-diol-9,10-epoxides of benzo [alpyrene are highly mutagenic in mammalian as well as in bacterial cells. 

Most animal steroids arise from cholesterol, which in turn is derived from squalene. This C30 triterpene, whose biosynthesis is described in Section B, is named after the dogfish Squalus in whose liver it accumulates as a result of blockage in oxidation to cholesterol. Squalene is also a prominent constituent of human skin lipids. Its conversion to cholesterol, which takes place in most animal tissues,117/154-156 is initiated by a microsomal enzyme system that utilized 02 and NAD-PH to form squalene 2,3-oxide (Fig. 22-6, step a). 

Fowler BA, Hook GER, Lucier GW. 1977. Tetrachlorodibenzo-p-dioxin induction of renal microsomal enzyme systems Ultrastructural effects on pars recta (S3) proximal tubule cells of the rat kidney. J Pharmacol Exp Ther 203 712-721. 

Strychnine is rapidly metabolized by the liver microsomal enzyme system requiring NADPH and O2. Five metabolites formed in vitro by rabbit fiver were isolated and identified as 2 -hydroxystrycfinine, 11,12-defiydrostrychnine, strychnine-21, 22-epoxide, 21,22-dihydroxy-22-hydrostrychnine, and strychnine-N-oxide which was the major metabolite and accounted for approximately 15% of the metabolized strychnine. AU other metabolites accounted for less than 1% (Mishimaetfl/., 1985). Similar metabolites were identified in rat urine where the major metabolite was strychnine-21,22-epoxide (Oguri et a/., 1989). The metabolic fate of strychnine in humans is unknown. 

Bennett, R.N., Donald, A.M., Dawson, G.W., Hick, A.J. and Wallsgrove, R.M. (1993) Aldoxime-forming microsomal enzyme systems involved in the biosynthesis of glucosinolates in oilseed rape leaves. Plant Physiol., 102, 1307-12. 

Cutler, A.J., Sternberg, M. and Corm, E.E. (1985) Properties of a microsomal enzyme system from Linum usitatissimum (linen flax), which oxidizes valine to acetone cyanohydrin and isoleucine to 2-methylbutanone cyanohydrin. Arch. Biochem. Biophys., 238,272-9. 

Du, L. and Halkier, B.A. (1996) Isolation of a microsomal enzyme system involved in glucosinolate biosynthesis from seedlings of Tropaeolum majus (L.). Plant Physiol, 111, 831-7. 

Unfortunately, the elimination of some drugs does not follow first-order kinetics. For example, the primary pathway of phenytoin elimination entails initial metabolism to form 5-(parahydroxyphenyl)-5-phenylhydantoin (p-HPPH), followed by glucuronide conjugation (Figure 2.8). The metabolism of this drug is not first order but follows Michaelis-Menten kinetics because the microsomal enzyme system that forms p-HPPH is partially saturated at phenytoin... 

This biotransformation process takes place principally in the liver, i.e. in the smooth endoplasmic reticulum, partly also in the mitochondria. The kidneys, lungs, intestine, muscles, spleen and skin are involved to a lesser degree in biotransformation. Through hydrolysis and reduction, the intestinal flora may also play a role in this metabolic process. Biotransformation is limited by the hepatic blood flow (= flow-limited elimination) and by the capacity of microsomal enzyme systems (= capacity-limited elimination). (80, 95)... 

Principle After the test substance has been demethylated by the microsomal enzyme system of the SER (cytochrome P 450), the labelled carbon atoms are catabolized to C02. The velocity of demethylation can be measured by determining the C02 value in expired air. Catabolization of aminopyrine is enhanced with elevated activity of the cytochrome P 450 and reduced accordingly due to the loss of liver cell volume. The metabolization is independent of perfusion. Exposure to radiation is minimal. 

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