Received for publication July 30, 2004.
Revised November 16, 2004.
Accepted for publication November 17, 2004.

Malathion bioactivation in the human liver: the contribution of different cytochrome P450 isoforms

Abstract

Among OPT pesticides, malathion is considered relatively safe for use in mammal. Its rapid degradation by carboxylesterases competes with the CYP-catalyzed formation of malaoxon, the toxic metabolite. However, impurities in commercial formulations are potent inhibitors of carboxylesterase, allowing a dramatic increase in malaoxon formation. Malathion desulfuration has been characterized in human liver microsomes (HLM) with a method based on AChE inhibition, able to detect nM levels of oxon. The active CYPs have been identified by means of a multifaceted strategy, including the use of c-DNA expressed human CYPs, correlation, immuno- and chemical inhibition studies in a panel of phenotyped HLM. HLM catalyzed malaoxon formation with a high level of variability (>200 fold). One or two components (K_mapp1=53-67 µM; K_mapp2=427-1721 µM) were evidenced, depending on the relative specific CYP content. Results from different approaches indicated that, at low malathion concentration, malaoxon formation is catalyzed by CYP1A2 and to a lesser extent 2B6, while the role of 3A4 is relevant only at high malathion levels. These results are in line with those found with chlorpyrifos, diazinon, azynphos-methyl and parathion, characterized by the presence of an aromatic ring in the molecule. Since malathion has linear chains as substituents at the thioether sulphur, it can be hypothesized that, independently from the chemical structure, OPTs are bioactivated by the same CYPs. These results also suggest that CYP1A2 and 2B6 can be considered as possible metabolic biomarkers of susceptibility to OPT-induced toxic effects at actual human exposure levels.

Key words: bioactivation, cholinesterases, CYP1A, CYP2B, CYP3A, cytochrome P450 catalyzed oxidations, cytochrome P450 isoforms, human CYP enzymes, insecticides, liver microsomes

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