Oxidation microsomal enzymes

Reduction of the toxicity of the phosphorothionate insecticide, EPN, to rats by nikethamide [135] is paralleled by a reduction in the cholinesterase inhibitory potency of this compound in vivo [136]. Nikethamide induces the synthesis of oxidative microsomal enzymes [137] concerned in the detoxication of EPN in both male and female rats [138]. Induction of these enzymes by the daily administration of phenobarbitone, 50 mg/kg for 5 days, reduces the acute toxicities of parathion, demeton-0, EPN, disulfoton, dioxathion. 

The experiments with deuterium-labeled nitrosamines illustrate two important points. One is that oxidation of nitrosamines takes place at more than one position in the molecule, and the outcome of the balance of such competing reactions probably is the determinant of carcinogenic potency. The second is that the reason for the failure of carcinogenesis to be mirrored in many cases by the microsomally activated bacterial mutagenicity is that there can be several metabolic steps leading to formation of the proximate carcinogenic agent and not all of these need necessarily involve microsomal enzymes. ... 

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. 

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... 

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). 

N-Me group is partly followed by A-demelhylalion, and the oxidation products can also undergo ester hydrolysis. As a result, several metabolic pathways convert bambuterol to terbutaline, and both plasma and liver microsomal enzymes may be involved. 

For foreign compounds, the majority of oxidation reactions are catalyzed by monooxygenase enzymes, which are part of the mixed function oxidase (MFO) system and are found in the SER (and also known as microsomal enzymes). Other enzymes involved in the oxidation of xenobiotics are found in other organelles such as the mitochondria and the cytosol. Thus, amine oxidases located in the mitochondria, xanthine oxidase, alcohol dehydrogenase in the cytosol, the prostaglandin synthetase system, and various other peroxidases may all be involved in the oxidation of foreign compounds. 

Aldehyde oxidase, a non-microsomal enzyme discussed in more detail below, may also be involved in the oxidation of quinoline to give 2-hydroxyquinoline (Fig. 4.14). The heterocyclic phthalazine ring in the drug hydralazine is oxidized by the microsomal enzymes to phthalazinone. The mechanism, which may involve nitrogen oxidation, is possibly involved in the toxicity of this drug (see chap. 7). Again, other enzymes may also be involved (Fig. 4.15). 

N-oxidation. The oxidation of nitrogen in tertiary amines, amides, imines, hydrazines, and heterocyclic rings may be catalyzed by microsomal enzymes or by other enzymes (see below). Thus the oxidation of trimethylamine to anN-oxide (Fig. 4.19) is catalyzed by the microsomal FAD-containing mono oxygenase. The N-oxide so formed may undergo enzyme-catalyzed decomposition to a secondary amine and aldehyde. This N to C transoxygenation is mediated by cytochromes P-450. The N-oxidation of 3-methylpyridine, however, is catalyzed by cytochromes P-450. This reaction may be involved in the toxicity of the analogue,... 

Amine oxidation. As well as the microsomal enzymes involved in the oxidation of amines, there are a number of other amine oxidase enzymes, which have a different subcellular distribution. The most important are the monoamine oxidases and the diamine oxidases. The monoamine oxidases are located in the mitochondria within the cell and are found in the liver and also other organs such as the heart and central nervous system and in vascular tissue. They are a group of flavoprotein enzymes with overlapping substrate specificities. Although primarily of importance in the metabolism of endogenous compounds such as 5-hydroxy try pt-amine, they may be involved in the metabolism of foreign compounds. 

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. 

Fish have a relatively poor ability for oxidative metabolism compared with the commonly used laboratory animals such as rats and mice. Insects such as flies have microsomal enzymes, and these are involved in the metabolism of the insecticide parathion to the more toxic paraoxon as discussed in the previous chapter (chap. 4, Fig. 25). 

The metabolite responsible for the carcinogenicity of benzo[a]pyrene (i.e., the ultimate carcinogenic metabolite) is the 7,8-dihydrodio 1-9,10-oxide. Some of the evidence is as follows the 7,8-dihydrodiol metabolite of benzo[a]pyrene binds more extensively to DNA after microsomal enzyme activation than other metabolites or benzo[alpyrene itself the nucleoside adducts formed are similar to those formed from benzo [a] pyrene itself the synthetic 7,8-dihydrodiol 9,10-oxides are highly mutagenic the 7,8-dihydrodiol is carcinogenic whereas the 4,5- and 9,10-epoxides are not. 

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). 

Metabolism of antipsychotics is through two mechanisms conjugation with glucuronic acid and oxidation by hepatic microsomal enzymes. Both mechanisms of metabolism and subsequent inactivation take place in the liver. Some degree of enzyme induction may occur because of prolonged use of antipsychotics, which may be responsible for increasing the rate of metabolism of these drugs. 

Hydration of epoxides catalyzed by epoxide hydrolase is involved in both detoxication and intoxication reactions. With high concentrations of styrene oxide as a substrate, the relative activity of hepatic microsomal epoxide hydrolase in several animal species is rhesus monkey > human = guinea pig > rabbit > rat > mouse. With some substrates, such as epoxidized lipids, the cytosolic hydrolase may be much more important than the microsomal enzyme. 

The mechanism of action of procarbazine is uncertain however, the drug inhibits the synthesis of DNA, RNA, and protein prolongs interphase and produces chromosome breaks. Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and H202, which may be responsible for DNA strand scission. A variety of other metabolites of the drug are formed that may be cytotoxic. One metabolite is a weak monoamine oxidase (MAO) inhibitor, and adverse side effects can occur when procarbazine is given with other MAO inhibitors. 

Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation by liver microsomal enzymes by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to 5-aminoimidazole-4-carboxamide, which is excreted in the urine, and diazomethane. The diazomethane generates a methyl carbonium ion that is believed to be the likely cytotoxic species. Dacarbazine is administered parenterally and is not schedule-dependent. It produces marked nausea, vomiting, and myelosuppression. Its major applications are in melanoma, Hodgkin s disease, and soft tissue sarcomas. 

The biotransformation of TCE in humans is carried out by the liver microsomal enzymes, hence requires NADPH and oxygen. Oxidation products found were chloral hydrate, trichloroacetic acid and trichloroethanol. The acid is excreted unchanged in the urine the ethanol is first converted to the glucuronate (ref. 65a). 

---