Testosterone hydroxylase in evaluating induction and suppression of murine CYP isoenzymes by fenarimol

Arch Toxicol. 1996;70(7):451-6. doi: 10.1007/s002040050298.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 Enzyme System / drug effects*
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Induction / drug effects
  • Female
  • Fungicides, Industrial / administration & dosage
  • Fungicides, Industrial / chemistry
  • Fungicides, Industrial / toxicity*
  • Injections, Intraperitoneal
  • Isoenzymes / drug effects*
  • Isoenzymes / metabolism
  • Kidney / drug effects
  • Kidney / enzymology
  • Lung / drug effects
  • Lung / enzymology
  • Male
  • Mice
  • Microsomes / drug effects*
  • Microsomes / enzymology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / toxicity*
  • Sex Factors
  • Steroid Hydroxylases / metabolism*

Substances

  • Fungicides, Industrial
  • Isoenzymes
  • Pyrimidines
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • testosterone 7-alpha-hydroxylase, hamster
  • fenarimol