TESTOSTERONE HYDROXYLASE IN EVALUATING INDUCTION AND SUPPRESSION OF MURINE CYP ISOENZYMES BY FENARIMOL

This study aimed to investigate the effect of single and repeated admi nistration of fenarimol on murine liver, kidney and lung microsomal CY P-catalyzed drug metabolism. The modulation of the regio- and stereo-s elective hydroxylation of testesterone by fenarimol was considered in evaluating cocarcinogenic properties. Induction or suppression of diff erent CYPs was recorded after a single dose of the fungicide. For exam ple, in liver, 6 beta-(mainly associated with CYP3A), 7 alpha- and 2 b eta-testosterone hydroxylase (TH) activities were induced up to 4.8-fo ld (7 alpha-TH) in female mice, at a dose of 150 mg/kg. In contrast, a t 150 and 300 mg/kg, 16 alpha-TH (CYP2B9), 17-TH (female) and 6 alpha- TH (CYP2A1 and 2B1, male) activities were appreciably reduced. In extr ahepatic tissues, the CYP modulation pattern was different, 16 alpha-T H being the only metabolite decreased (lung, male). In kidney, 16 beta -TH and 17-TH activities were increased up to 5.8-fold in female mice (lowest dose), while in lung 6 alpha-TH and 7 alpha-TH activities were induced up to 6- and 7-fold, respectively (both doses). Repeated trea tment (150 mg/kg for 3 days) was able markedly to induce all steroid h ydroxylations, up to 78- fold in 2 alpha-TH activity (male liver). In conclusion, fenarimol has a complex pattern of CYP induction or suppre ssion in various tissues of both sexes, suggesting the possible toxic, cotoxic/cocarcinogenic and promoting potential of this fungicide.