Tags

Type your tag names separated by a space and hit enter

Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s.
Toxicol Appl Pharmacol. 2005 Jun 15; 205(3):237-46.TA

Abstract

The drug-toxicant interaction between the antidepressant imipramine (IMI) and three organophosphorothionate pesticides (OPTs), to which humans may be chronically and simultaneously exposed, has been investigated in vitro. Concentrations of IMI (2-400 microM) and OPTs (< or =10 microM) representative of actual human exposure have been tested with recombinant human CYPs and human liver microsomes (HLM). The different CYPs involved in IMI demethylation to the pharmacologically active metabolite desipramine (DES) were CYP2C19 > CYP1A2 > CYP3A4. The OPTs significantly inhibited (up to >80%) IMI bioactivation catalyzed by the recombinant CYPs tested, except CYP2D6, and by HLM; the inhibition was dose-dependent and started at low pesticide concentrations (0.25-2.5 microM). The OPTs, having lower K(m) values, efficiently competed with IMI for the enzyme active site, as in the case of CYP2C19. However, with CYP1A2 and CYP3A4, a time- and NADPH-dependent mechanism-based inactivation also occurred, consistently with irreversible inhibition due to the release of the sulfur atom, binding to the active CYP during OPT desulfuration. At low IMI and OPT concentrations, lower IC50 values have been obtained with recombinant CYP1A2 (0.7-1.1 microM) or with HLM rich in 1A2-related activity (2-10.8 microM). The K(i) values (2-14 microM), independent on substrate concentrations, were quite low and similar for the three pesticides. Exposure to OPTs during IMI therapeutic treatments may lead to decreased DES formation, resulting in high plasma levels of the parent drug, eventual impairment of its pharmacological action and possible onset of adverse drug reactions (ADRs).

Authors+Show Affiliations

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

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15922009

Citation

Di Consiglio, Emma, et al. "Organophosphorothionate Pesticides Inhibit the Bioactivation of Imipramine By Human Hepatic Cytochrome P450s." Toxicology and Applied Pharmacology, vol. 205, no. 3, 2005, pp. 237-46.
Di Consiglio E, Meneguz A, Testai E. Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s. Toxicol Appl Pharmacol. 2005;205(3):237-46.
Di Consiglio, E., Meneguz, A., & Testai, E. (2005). Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s. Toxicology and Applied Pharmacology, 205(3), 237-46.
Di Consiglio E, Meneguz A, Testai E. Organophosphorothionate Pesticides Inhibit the Bioactivation of Imipramine By Human Hepatic Cytochrome P450s. Toxicol Appl Pharmacol. 2005 Jun 15;205(3):237-46. PubMed PMID: 15922009.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s. AU - Di Consiglio,Emma, AU - Meneguz,Annarita, AU - Testai,Emanuela, PY - 2004/09/20/received PY - 2004/10/13/accepted PY - 2005/6/1/pubmed PY - 2005/8/3/medline PY - 2005/6/1/entrez SP - 237 EP - 46 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 205 IS - 3 N2 - The drug-toxicant interaction between the antidepressant imipramine (IMI) and three organophosphorothionate pesticides (OPTs), to which humans may be chronically and simultaneously exposed, has been investigated in vitro. Concentrations of IMI (2-400 microM) and OPTs (< or =10 microM) representative of actual human exposure have been tested with recombinant human CYPs and human liver microsomes (HLM). The different CYPs involved in IMI demethylation to the pharmacologically active metabolite desipramine (DES) were CYP2C19 > CYP1A2 > CYP3A4. The OPTs significantly inhibited (up to >80%) IMI bioactivation catalyzed by the recombinant CYPs tested, except CYP2D6, and by HLM; the inhibition was dose-dependent and started at low pesticide concentrations (0.25-2.5 microM). The OPTs, having lower K(m) values, efficiently competed with IMI for the enzyme active site, as in the case of CYP2C19. However, with CYP1A2 and CYP3A4, a time- and NADPH-dependent mechanism-based inactivation also occurred, consistently with irreversible inhibition due to the release of the sulfur atom, binding to the active CYP during OPT desulfuration. At low IMI and OPT concentrations, lower IC50 values have been obtained with recombinant CYP1A2 (0.7-1.1 microM) or with HLM rich in 1A2-related activity (2-10.8 microM). The K(i) values (2-14 microM), independent on substrate concentrations, were quite low and similar for the three pesticides. Exposure to OPTs during IMI therapeutic treatments may lead to decreased DES formation, resulting in high plasma levels of the parent drug, eventual impairment of its pharmacological action and possible onset of adverse drug reactions (ADRs). SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/15922009/Organophosphorothionate_pesticides_inhibit_the_bioactivation_of_imipramine_by_human_hepatic_cytochrome_P450s_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(04)00479-X DB - PRIME DP - Unbound Medicine ER -