CARBARYL INDUCES CYP1A1 GENE-EXPRESSION IN HEPG2 AND HACAT CELLS BUT IS NOT A LIGAND OF THE HUMAN HEPATIC AH RECEPTOR

In spite of increasing numbers of insecticides used in agriculture, th ere are serious concerns regarding the potential risks of exposure to these agents. Carbaryl is one of the most important carbamate insectic ides and has been used for about 30 years to control a wide range of p ests. The study was designed to investigate if, among various insectic ides currently used in world agriculture, this compound could induce h uman CYP1A1, an enzyme known to play an important role in the chemical activation of xenobiotics to genotoxic derivatives. Studies on HepG2 and HaCaT cell lines showed that carbaryl is capable of increasing, in a dose-dependent manner, both the ethoxyresorufin rufin-O-dee, O-deet hylase activity and the steady-state concentrations of CYP1A1 mRNA, su ggesting a transcriptional activation of this gene. When a-naphthoflav one, a partial Ah receptor (AhR) antagonist, and 8-methoxypsoralen, wh ich interferes with the binding of activated AhR to the xenobiotic res ponsive element (XRE), were added to the cultures, CYP1A1 induction wa s suppressed. However, competitive binding studies using the 9S enrich ed fraction of human cytosol indicated that carbaryl did not displace [H-3]TCDD from AhR. These data, together with the activation of a XRE- directed CAT reporter gene by carbaryl, suggest that induction of CYP1 A1 involves the participation of the AhR and the XRE, but is not media ted by a direct carbaryl-receptor interaction. An alternative ligand-i ndependent mechanism should be considered. Therefore, although carbary l concentration in food is very low, care should be taken because of i ts possible adverse effects in human health through liver and skin, gi ven the well established toxicological importance of CYP1A1 induction. (C) 1997 Academic Press.