Thus, the Mo center is involved in the oxidation of the substrate. In the
mechanism, the source of the oxygen atom inserted into the substrate is H 2 O
instead of O 2 (as with P450 and FMO). The list of substrates includes some
endogenous and xenobiotic aldehydes, and various heterocycles, including purines,
pyridines, pyrimidines, pteridines, and others. Xanthine is a substrate for xanthine
dehydrogenase but not aldehyde oxidase;purines are substrates for both.
As with FMO, this enzyme has some inherent instability and care should be
exercised in processing tissue samples of the presence of this enzyme is an issue.
Aldehyde oxidase is a true ‘‘oxidase,’’ in that it transfers electrons to O 2 (to
form H 2 O 2 ). The literature contains numerous reports about (milk) xanthine
oxidase; subsequent work revealed that this is really xanthine dehydrogenase
(Rajagopalan, 1997), which is readily converted to an oxidase by proteolysis or
modification of sulfides.
Rodents contain additional genes in this family but humans have only the
two genes mentioned here (Kurosaki et al., 2004).
2.5.5 Peroxidases
A variety of peroxidases are found in various mammalian cells, including
prostaglandin synthases, myeloperoxidase, lipoxygenases, and eosinophile
peroxidases (Marnett et al., 1997). The reactions have some similarity to
events in P450 chemistry in the context that reactions involve high rodent FeO
chemistry. With regard to drug metabolism, the basic reaction of interest is
RXþRX!...and the reactions of the radical RX include radical propagation, dimer
formation, dealkylation, and so on (Marnett et al., 1997). Other possible
reactions include oxygenation (R!RO) and the formation of reactive halides,
-H+-H+N
CH 3N
CH 3N
CH 3N
CH 3N
CH 3-2e_ -e-•• •• ••+MPTP MPDP MPP++-H+, -e-FIGURE 2.7 Oxidation ofN-methyl, 4-phenyl-1,2,5,6-tetrahydropyridine by MAO
(Chiba et al., 1985).
24 OXIDATIVE, REDUCTIVE, AND HYDROLYTIC METABOLISM OF DRUGS