QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.104.001693v1 33/3/295    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buratti, F. M. Articles by Testai, E. Search for Related Content PubMed PubMed Citation Articles by Buratti, F. M. Articles by Testai, E.

MALATHION BIOACTIVATION IN THE HUMAN LIVER: THE CONTRIBUTION OF DIFFERENT CYTOCHROME P450 ISOFORMS

Environment and Primary Prevention Department (F.M.B., A.D.A., E.T.) and Drug Research and Evaluation Department (M.T.V., A.M.), Istituto Superiore di Sanità, Rome, Italy

Among organophosphorothioate (OPT) pesticides, malathion is considered relatively safe for use in mammals. Its rapid degradation by carboxylesterases competes with the cytochrome P450 (P450)-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 (HLMs) with a method based on acetylcholinesterase inhibition that is able to detect nanomolar levels of oxon. The active P450 isoforms have been identified by means of a multifaceted strategy, including the use of cDNA-expressed human P450s and correlation, immunoinhibition, and chemical inhibition studies in a panel of phenotyped HLMs. HLMs 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 P450 content. Results from different approaches indicated that, at low malathion concentration, malaoxon formation is catalyzed by CYP1A2 and, to a lesser extent, 2B6, whereas 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 sulfur, it can be hypothesized that, independently from the chemical structure, OPTs are bioactivated by the same P450s. 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.

This article has been cited by other articles:

				H.-K. Lee, J.-K. Moon, C.-H. Chang, H. Choi, H.-W. Park, B.-S. Park, H.-S. Lee, E.-C. Hwang, Y.-D. Lee, K.-H. Liu, et al. STEREOSELECTIVE METABOLISM OF ENDOSULFAN BY HUMAN LIVER MICROSOMES AND HUMAN CYTOCHROME P450 ISOFORMS Drug Metab. Dispos., July 1, 2006; 34(7): 1090 - 1095. [Abstract] [Full Text] [PDF]