Oxidation cytochrome P450 biotransformations

Haloperidol is a butyrophenone neuroleptic drug. The enzymes involved in its biotransformation include oxidative cytochrome P450 isozymes, carbonyl reductase, and uridine diphosphoglucose glucuronosyltransferase (1). It is mainly cleared by glucuronidation. 

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

Valuable metabolic insights have been gained from in-depth studies of phenytoin (diphenylhydantoin, 10.21), whose main biotransformation pathway is by cytochrome P450 catalyzed phenyl oxidation. Incubations with rat liver 9000 g supernatant produced the para-phenol (4 -hydroxyphenytoin) as the major metabolite, and the dihydrodiol in smaller proportions. Minute amounts of other metabolites were also detected, e.g., the meto-phenol and the 3-O-mclhylcalcchol. Studies in rats confirmed the urinary excretion, in decreasing order of importance, of the para-phenol, the dihydrodiol, and the 3-O-mclhylcalcchol metabolites [78][79],... 

Metabolism/Excretion - Nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. 

For most drugs, oxidative biotransformation is performed primarily by the mixed-function oxidase enzyme system, which is present predominantly in the smooth endoplasmic reticulum of the liver. This system comprises (1) the enzyme NADPH cytochrome P450 reductase (2) cytochrome P450, a family of heme-containing proteins that catalyze a variety of oxidative and reductive reactions and (3) a phospholipid bilayer that facilitates interaction between the two proteins. Important exceptions to this rule are ethyl alcohol and caffeine, which are oxidatively metabolized by enzymes primarily present in the soluble, cytosolic fraction of the liver. 

At this time I was interested in the natural tolerance of houseflies to structural analogues of dieldrin and, with Harrison, I soon showed that whereas tolerance to cyclodienes was often related to oxidative detoxication and could be reduced or eliminated by benzodioxole synergists, dieldrin-resistance in houseflies did not respond to synergism and was apparently not a consequence of oxidative detoxication (33) Several laboratories (for their subsequent reviews see 34-36) confirmed the importance of oxidative biotransformations in insects and in 1964-5, at Slough, J. W Ray showed that microsomal preparations from houseflies and other insects contained cytochrome P450 (37) Thus, the links between insect and mammalian biochemical pharmacology were finally and firmly established. 

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