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The participation of human hepatic P450 isoforms, flavin-containing monooxygenases and aldehyde oxidase in the biotransformation of the insecticide fenthion.
Toxicol Appl Pharmacol. 2008 Dec 01; 233(2):343-52.TA

Abstract

Although fenthion (FEN) is widely used as a broad spectrum insecticide on various crops in many countries, very scant data are available on its biotransformation in humans. In this study the in vitro human hepatic FEN biotransformation was characterized, identifying the relative contributions of cytochrome P450 (CYPs) and/or flavin-containing monooxygenase (FMOs) by using single c-DNA expressed human enzymes, human liver microsomes and cytosol and CYP/FMO-specific inhibitors. Two major metabolites, FEN-sulfoxide and FEN-oxon (FOX), are formed by some CYPs although at very different levels, depending on the relative CYP hepatic content. Formation of further oxidation products and the reduction of FEN-sulfoxide back to FEN by the cytosolic aldehyde oxidase enzyme were ruled out. Comparing intrinsic clearance values, FOX formation seemed to be favored and at low FEN concentrations CYP2B6 and 1A2 are mainly involved in its formation. At higher levels, a more widespread CYP involvement was evident, as in the case of FEN-sulfoxide, although a higher efficiency of CYP2C family was suggested. Hepatic FMOs were able to catalyze only sulfoxide formation, but at low FEN concentrations hepatic FEN sulfoxidation is predominantly P450-driven. Indeed, the contribution of the hepatic isoforms FMO(3) and FMO(5) was generally negligible, although at high FEN concentrations FMO's showed activities comparable to the active CYPs, accounting for up to 30% of total sulfoxidation. Recombinant FMO(1) showed the highest efficiency with respect to CYPs and the other FMOs, but it is not expressed in the adult human liver. This suggests that FMO(1)-catalysed sulfoxidation may represent the major extra-hepatic pathway of FEN biotransformation.

Authors+Show Affiliations

Environment and Primary Prevention Department, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18845175

Citation

Leoni, Claudia, et al. "The Participation of Human Hepatic P450 Isoforms, Flavin-containing Monooxygenases and Aldehyde Oxidase in the Biotransformation of the Insecticide Fenthion." Toxicology and Applied Pharmacology, vol. 233, no. 2, 2008, pp. 343-52.
Leoni C, Buratti FM, Testai E. The participation of human hepatic P450 isoforms, flavin-containing monooxygenases and aldehyde oxidase in the biotransformation of the insecticide fenthion. Toxicol Appl Pharmacol. 2008;233(2):343-52.
Leoni, C., Buratti, F. M., & Testai, E. (2008). The participation of human hepatic P450 isoforms, flavin-containing monooxygenases and aldehyde oxidase in the biotransformation of the insecticide fenthion. Toxicology and Applied Pharmacology, 233(2), 343-52. https://doi.org/10.1016/j.taap.2008.09.004
Leoni C, Buratti FM, Testai E. The Participation of Human Hepatic P450 Isoforms, Flavin-containing Monooxygenases and Aldehyde Oxidase in the Biotransformation of the Insecticide Fenthion. Toxicol Appl Pharmacol. 2008 Dec 1;233(2):343-52. PubMed PMID: 18845175.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The participation of human hepatic P450 isoforms, flavin-containing monooxygenases and aldehyde oxidase in the biotransformation of the insecticide fenthion. AU - Leoni,Claudia, AU - Buratti,Franca M, AU - Testai,Emanuela, Y1 - 2008/09/19/ PY - 2008/07/22/received PY - 2008/09/04/revised PY - 2008/09/06/accepted PY - 2008/10/11/pubmed PY - 2008/12/17/medline PY - 2008/10/11/entrez SP - 343 EP - 52 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 233 IS - 2 N2 - Although fenthion (FEN) is widely used as a broad spectrum insecticide on various crops in many countries, very scant data are available on its biotransformation in humans. In this study the in vitro human hepatic FEN biotransformation was characterized, identifying the relative contributions of cytochrome P450 (CYPs) and/or flavin-containing monooxygenase (FMOs) by using single c-DNA expressed human enzymes, human liver microsomes and cytosol and CYP/FMO-specific inhibitors. Two major metabolites, FEN-sulfoxide and FEN-oxon (FOX), are formed by some CYPs although at very different levels, depending on the relative CYP hepatic content. Formation of further oxidation products and the reduction of FEN-sulfoxide back to FEN by the cytosolic aldehyde oxidase enzyme were ruled out. Comparing intrinsic clearance values, FOX formation seemed to be favored and at low FEN concentrations CYP2B6 and 1A2 are mainly involved in its formation. At higher levels, a more widespread CYP involvement was evident, as in the case of FEN-sulfoxide, although a higher efficiency of CYP2C family was suggested. Hepatic FMOs were able to catalyze only sulfoxide formation, but at low FEN concentrations hepatic FEN sulfoxidation is predominantly P450-driven. Indeed, the contribution of the hepatic isoforms FMO(3) and FMO(5) was generally negligible, although at high FEN concentrations FMO's showed activities comparable to the active CYPs, accounting for up to 30% of total sulfoxidation. Recombinant FMO(1) showed the highest efficiency with respect to CYPs and the other FMOs, but it is not expressed in the adult human liver. This suggests that FMO(1)-catalysed sulfoxidation may represent the major extra-hepatic pathway of FEN biotransformation. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/18845175/The_participation_of_human_hepatic_P450_isoforms_flavin_containing_monooxygenases_and_aldehyde_oxidase_in_the_biotransformation_of_the_insecticide_fenthion_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(08)00376-1 DB - PRIME DP - Unbound Medicine ER -