Introduction

Environmental exposure to foreign compounds that might be harmful to normal biological function has necessitated the development of a generalized defense system in virtually all higher life forms. To cope with the challenges that exposure brings requires that the system be sophisticated enough to effectively operate on chemical entities to which the living organism has never been exposed. This has been partially achieved by the evolution of the group of enzyme systems outlined in Table 1. Virtually any organic molecule can be transformed by one or more of the enzymes in this group. Most are oxidoreductases, and thus have dual reaction modes. They can activate and utilize molecular oxygen to oxidize xenobiotics or utilize electrons supplied by cofactors to reduce xenobiotics. For a few, reduction is the preferred course of reaction. The products invariably have altered biological properties since they are structurally distinct from the parents. Their increased polarity results in their increased water solubility and more rapid elimination from the body. An excellent discussion of the role these enzymes play in drug metabolism can be found in the book by Testa.1

Table 1 General properties of the major oxidoreductases that catalyze the metabolism of xenobiotics in the human

Enzyme system

Size (kDa)

Location

Cofactors

Primary substrates Site of attack

Gyp" (multiple -50

isoforms in three families)

FMOc (six isoforms) -60

XORf (two interconvertible forms)

Aldehyde oxidase

Aldehyde dehydrogenase (many isoforms)

Alcohol dehydrogenase (superfamily)

AKRg (superfamily)

Garbonyl reductase (superfamily)

-300 (homodimeric)

-300 (homodimeric)

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