title: Testosterone hydroxylase in evaluating induction and suppression of murine CYP isoenzymes by fenarimol.
abstract: This study aimed to investigate the effect of single and repeated administration of fenarimol on murine liver, kidney and lung microsomal CYP-catalyzed drug metabolism. The modulation of the regio- and stereo-selective hydroxylation of testosterone by fenarimol was considered in evaluating cocarcinogenic properties. Induction or suppression of different CYPs was recorded after a single dose of the fungicide. For example, in liver, 6 beta-(mainly associated with CYP3A), 7 alpha- and 2 beta-testosterone hydroxylase (TH) activities were induced up to 4.8-fold (7 alpha-TH) in female mice, at a dose of 150 mg/kg. In contrast, at 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 extrahepatic tissues, the CYP modulation pattern was different, 16 alpha-TH 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 treatment (150 mg/kg for 3 days) was able markedly to induce all steroid hydroxylations, up to 78-fold in 2 alpha-TH activity (male liver). In conclusion, fenarimol has a complex pattern of CYP induction or suppression in various tissues of both sexes, suggesting the possible toxic, cotoxic/cocarcinogenic and promoting potential of this fungicide.
authors: Department of Pharmacology, University of Bologna, Italy.
authors: M
authors: M
authors: Paolini
authors: L
authors: L
authors: Pozzetti
authors: R
authors: R
authors: Mesirca
authors: A
authors: A
authors: Sapone
authors: G
authors: G
authors: Cantelli-Forti
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D012737:Sex Factors; D013250:Steroid Hydroxylases / Q000378:metabolism*
chemical_list: D005659:Fungicides, Industrial; D007527:Isoenzymes; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster; C033789:fenarimol