P450-catalyzed metabolic pathways

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],... 

The most important example to be discussed here is that of the drug chloramphenicol (11.39, R = 2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophen-yl)ethyl, Fig. 11.7), the many metabolic pathways of which have yielded a wealth of information [75], The dichloroacetyl moiety is especially of interest in that dechlorination proceeds by three proven routes glutathione-dependent dechlorination, cytochrome P450 catalyzed oxidation, and hydrolysis. Of particular value is that the oxidative and hydrolytic routes can be unambiguously distinguished by at least one product, as shown in Fig. 11.7. Oxidation at the geminal H-atom produces an unstable (dichloro)hydroxyacet-amido intermediate that spontaneously eliminates HC1 to yield the oxamoyl... 

There are a few data in the literature to suggest that the hydrolysis of aliphatic nitriles occurs in mammals, but only as a minor or even undetectable pathway in competition with oxidative denitrilation. For example, benzyl cyanide (11.80, Fig. 11.12) undergoes cytochrome P450 catalyzed hydroxy-lation to mandelonitrile (11.81), from which cyanide and benzaldehyde are produced, the latter being oxidized to benzoic acid (11.83) [118]. However, a careful metabolic study of mandelonitrile has shown that, in the rat, this pathway accounts for ca. 90% and not 100% of the dose [122], Only ca. 10% of orally administered benzyl cyanide was converted to mandelic acid (11.82, Fig. 11.12) by hydrolysis of the CN group. 

The major oxidative drug-metabolizing pathway is catalyzed by cytochrome P450 enzymes (Mulder, 2006). The abbreviation CYP is typically used in this context. More than 60 CYPs have been identified. These are identified by up to four characters (letters or numbers). For example, in the term CYP2A4 4 the letters and numbers indicate the following ... 

Metabolic activation of aflatoxin Bh belonging to the class of my cotoxins, is catalyzed by cytochrome P450. The metabolic conversion of this compound can follow many pathways however, only the epoxidation in position 8/9 produces the ultimate carcinogen ... 

In vitro metabolic studies with rodent and human liver microsomal prepara- tions have established that MPTP undergoes both oxidative N-demethylation and C-6 (allylic) oxidation in reactions that are -nicotinamide adenine dinucleotide phosphate (NADPH) dependent and therefore likely to be cytochrome P-450 catalyzed (Weissman et al. 1985 Ottoboni et al. 1990). Although the latter transformation can lead to the toxic pyridinium metabolite MPP, the cytochrome P450-catalyzed pathway is unlikely to contribute significantly to the neurotoxicity of MPTP. As mentioned above, liver aldehyde oxidase diverts the inter-mediate dihydropyridinium metabolite away from pyridinium ion formation by catalyzing the conversion of structure 40 to the nontoxic lactim structure 41. Further-more, even if formed in the periphery, the polar pyridinium metabolite would have limited access to the central nervous system (CNS). The low... 

Figure 1 shows the principal metabolic pathways of B tP (a representative PAH) and the formation of some conjugates. In the interest of simplicity, further metabolic transformations, such as the P450 catalyzed oxidation of phenols to phenol-epoxides, conversion of phenols to phenol-dihydrodiols, all the enzymatic steps, and the stereochemistry of the metabolites are omitted. 

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