Interspecies differences in metabolism of heterocyclic aromatic amines by rat and human P450 1A2
Introduction
The potency of a carcinogen is dependent upon the balance between enzyme pathways that catalyze activation and detoxication. For HAAs, cytochrome P450 and phase II enzymes are involved in both metabolic processes. The principal pathways of HAA detoxication in animal species and humans include: cytochrome P450-mediated ring oxidation, followed by conjugation to sulfate or glucuronic acid, and direct phase II conjugation to the exocyclic amine groups (Fig. 1) [1]. Metabolic activation occurs by P450-mediated N-oxidation of the exocyclic amine groups to form the N-hydroxy intermediates which may react directly with DNA [1].
The comparison between experimental animals and human enzymes involved in HAA metabolislm is essential for the extrapolation of animal carcinogenicity data to assess human health risk, and consideration of species differences in enzyme expression and catalytic activities is important [2]. Cytochrome P450 1A2 is a key enzyme involved in the activation of HAAs in humans and rats, a species which succumbs to tumors following long-term feeding studies with HAAs [3]. This article will review our recent studies on the variable expression of P450 1A2 in rat and human liver samples and the relative catalytic activities and regioselectivity of rat and human P450 1A2 in oxidation of MeIQx and PhIP [4], two of the most abundant HAAs found in cooked foods [5].
Section snippets
Results
The major P450 oxidation pathways and phase II conjugation pathways of MeIQx and PhIP are depicted in Fig. 1. Rat liver microsomes and rat P450 1A2 catalyze oxidation of the heterocyclic ring (detoxication) and the exocyclic amine groups (activation) of these HAAs, while human liver microsomes and recombinant human P450 1A2 principally catalyze N-oxidation and oxidation of the 8-CH3 group of MeIQx to a lesser extent [4]. The differences in regioselectivity between rat and human P450-mediated
Discussion
Rat and human P450 1A2 are 75% identical in amino acid sequence [2], and these changes in sequence are sufficient to account for profound effects on catalytic activities and regioselectivity of HAA oxidation. Catalytic activity is also highly dependent upon the chemical structure of the substrate as shown by methoxoyresorufin, which displayed similar kinetic parameters for the rat and human P450 1A2 counterparts.
The relatively high levels of P450 1A2 expression in human liver tissue and
Acknowledgements
This work was supported in part by United States Public Health Service Grant R35 CA44353 and P30 ESOO267
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