Organophosphorothionate pesticides inhibit the bioactivation of imipramine by human hepatic cytochrome P450s.
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).
Di Consiglio
Emma
E
Environment and Primary Prevention Department, Mechanisms of Toxicity Unit, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161 Rome, Italy.
Meneguz
Annarita
A
Testai
Emanuela
E
D001711:Biotransformation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007099:Imipramine / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000009:adverse effects* / Q000737:chemistry; D010089:Oxidoreductases, N-Demethylating; D010575:Pesticides / Q000009:adverse effects / Q000737:chemistry
D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D009946:Organothiophosphorus Compounds; D010575:Pesticides; D003577:Cytochrome P-450 Enzyme System; D010089:Oxidoreductases, N-Demethylating; D007099:Imipramine