Cytochrome P450, drug metabolizing enzymes and arachidonic acid metabolism in bovine ocular tissues.

Abstract

Little information is available on drug metabolizing enzymes in ocular tissues. We investigated the presence of various cytochrome P450 isozymes by measuring different drug metabolizing enzymes, i.e., aryl hydrocarbon hydroxylase, 7 ethoxycoumarin-o-deethylase and benzphetamine demethylase activities in ciliary body, corneal epithelium and endothelium, retina and retinal pigment epithelium. Our results demonstrate that the ciliary body and the retinal pigment epithelium possess the highest activities of cytochrome P450-dependent monooxygenases in the eye. The highest activity of drug metabolizing enzymes is accompanied by high activity of NADPH cytochrome P450 (C) reductase, an integral component of this enzyme system. Heme oxygenase, a key enzyme for the regulation of heme availability to hemoproteins such as cytochrome P450 also demonstrate high activity in these two ocular tissues. Although the corneal epithelium has a lower activity of drug metabolizing enzymes, it possesses the highest activity of cytochrome P450 species capable of metabolizing arachidonic acid to biologically active compounds, whereas the other ocular tissues possess cyclooxygenase as the main microsomal enzyme that metabolizes arachidonic acid. Whether the observed catalytic activities of drug metabolizing enzymes seen in ocular tissues are associated with major or minor forms of cytochrome P450 is not yet know. However, the specialized location of cytochrome P450 isozymes in ocular tissues suggests a physiological function related to activation of endogenous compounds such as arachidonic acid, in addition to detoxification of drugs.