Cytochrome microsomal oxidation

Iron complexes or microsomal nonheme iron are undoubtedly obligatory components in the microsomal oxidation of many organic compounds mediated by hydroxyl radicals. In 1980, Cohen and Cederbaum [27] suggested that rat liver microsomes oxidized ethanol, methional, 2-keto-4-thiomethylbutyric acid, and dimethylsulfoxide via hydrogen atom abstraction by hydroxyl radicals. Then, Ingelman-Sundberg and Ekstrom [28] assumed that the hydroxylation of aniline by reconstituted microsomal cytochrome P-450 system is mediated by hydroxyl radicals formed in the superoxide-driven Fenton reaction. Similar conclusion has been made for the explanation of inhibitory effects of pyrazole and 4-methylpyrazole on the microsomal oxidation of ethanol and DMSO [29],... 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

Microsomal oxidation of amines and phenols may proceed by different ways. For example, it has been shown [42] that phentermine (2-methyl-l-phenyl-2-propylamine) is hydro-xylated to /V-hydroxyphcntcrminc by rat liver cytochrome P-450 system through a normal cytochrome P-450 way ... 

Surbrook, S.E., and M.J.Olson. 1992. Dominant role of cytochrome P-450 2E1 in human hepatic microsomal oxidation of the CFC-substitute 1,1,1,2-tetrafluoroethane. Drug Metab. Dispos. 20 518-524. 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by hepatic microsomal oxidation and then undergo glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. Drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., erythromycin, nefazodone, fluvoxamine, and ketoconazole) reduce the clearance of triazolam and increase its plasma concentrations."... 

Interactions of methylenedioxyphenyl compounds with cytochrome P-450 and effects on microsomal oxidation. In E. Hodgson, J.R. Bend, and R.M. Philpot (eds.). Reviews in Biochemical Toxicology, Vol. 6. Elsevier, Amsterdam, pp. 27-63. 

Murray M, Butler AM (1994) Hepatic biotransformation of parathion role of cytochrome P450 in NADPH- and NADH-mediated microsomal oxidation in vitro. Chem Res Toxicol 7 792-799... 

Physiologically, microsomal oxidation via the cytochromes appears to serve for the lipophilic oxidation of steroids, fatty acids, heme, and drugs. The microsomal cytochromes and smooth endoplasmic reticulum may be controlled in part by steroids. For example, the relatively high production of heme by normal liver suggests that there may be natural 5/i-H steroids that normally serve to maintain a certain rate of heme synthesis by inducing the synthesis of ALA-synthetase. An... 

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