Induction of drug metabolizing enzyme and drug transporter expression by antifungal triazole pesticides in human HepaSH hepatocytes

Triazole pesticides are widely used fungicides, to which humans are rather highly exposed. They are known to activate drug-sensing receptors regulating expression of hepatic drug metabolizing enzymes and drug transporters, thus suggesting that the hepatic drug detoxification system is modified by these agrochemicals. To investigate this hypothesis, the effects of 9 triazole fungicides towards expression of drug metabolizing enzymes and transporters were characterized in cultured human HepaSH cells, that are human hepatocytes deriving from chimeric humanized liver TK-NOG mice. Most of triazoles used at 10 μM were found to act as inducers of cytochrome P-450 (CYP) 1A1, CYP1A2, CYP2B6, CYP3A4 and UDP-glucuronosyltransferase 1A1 mRNA levels and of CYP3A4 protein; some triazoles also enhanced mRNA expression of the canalicular transporters P-glycoprotein/MDR1, multidrug resistance-associated protein 2 and breast cancer resistance protein. Triazoles however concomitantly inhibited CYP2B6 and CYP3A4 activities and thus appeared as dual regulators of these CYPs, being both inducers of their expression and inhibitors of their activity. The inducing effect however predominated, at least for bromuconazole, propiconazole and tebuconazole. Bromuconazole was moreover predicted to enhance CYP2B6 and CYP3A4 expression in humans exposed to this fungicide in a chronic, acute or occupational context. These data demonstrate that key-actors of the human hepatic detoxification system are impacted by triazole pesticides, which may have to be considered for the risk assessment of these agrochemicals. They additionally highlight that the use of human HepaSH cells as surrogates to primary human hepatocytes represents an attractive and promising way for studying hepatic effects of environmental chemicals.