Testosterone hydroxylase in evaluating induction and suppression of murine CYP isoenzymes by fenarimol.
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.
Paolini
M
M
Department of Pharmacology, University of Bologna, Italy.
Pozzetti
L
L
Mesirca
R
R
Sapone
A
A
Cantelli-Forti
G
G
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*
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