Molecular non-genetic biomarkers related to Fenarimol cocarcinogenesis: organ- and sex-specific CYP induction in rat

Cancer Lett. 1996 Mar 29;101(2):171-8. doi: 10.1016/0304-3835(96)04130-4.

Abstract

Selective biochemical markers of effect have been used to evaluate some non-genotoxic cocarcinogenic properties of Fenarimol. Several CYP-dependent reactions have been monitored in liver, kidney and lung microsomes of male and female Sprague-Dawely rats treated (i.p.) with 200 or 400 mg/kg body wt dose of this pesticide. Highly specific substrates were used as probes of various isoforms, such as CYP1A1, 1A2, 2B1, 2E1 and 3A. A complex pattern of CYP induction, including organ- and sex-related differences in the inductive response by Fenarimol, has been recorded in this investigation, the kidney (mainly male) being more responsive when compared to other tissues. A 6.6-fold increase in the 2B1-like activity, probed by dealkylation of pentoxyresorufin was observed in the liver at a higher dose. On the contrary, a marked induction of CYP1A1 mediated ethoxyresorufin O-deethylase activity, ranging from 20- to 35-fold in female and male, respectively, was observed in the kidney at a lower dose tested. In the lung, at a higher dose, the p-nitrophenol hydroxylase activity (2E1) was enhanced up to 3.5-fold in male animals, whereas the 3A-like activity, probed by the N-demethylation of aminopyrine, was induced up to 2.6-fold in females. A weak, although significant reduction of CYP2B1 isoforms in lung was also recorded. Taken together, these data corroborated by means of Western immunoblotting analysis (using rabbit polyclonal antibodies anti-CYP 2B1/2, 1A1, 2E1, and 3A1/2) indicate a possible cotoxic, comutagenic cocancerogenic and promoting potential of this fungicide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 7-Alkoxycoumarin O-Dealkylase / biosynthesis
  • 7-Alkoxycoumarin O-Dealkylase / drug effects
  • Aminopyrine N-Demethylase / biosynthesis
  • Aminopyrine N-Demethylase / drug effects
  • Animals
  • Cocarcinogenesis
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP2B1
  • Cytochrome P-450 CYP2E1
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / drug effects*
  • Female
  • Fungicides, Industrial / toxicity*
  • Kidney / drug effects*
  • Kidney / enzymology
  • Liver / drug effects*
  • Liver / enzymology
  • Lung / drug effects*
  • Lung / enzymology
  • Male
  • Mixed Function Oxygenases / biosynthesis
  • Mixed Function Oxygenases / drug effects
  • Oxidoreductases / biosynthesis
  • Oxidoreductases / drug effects
  • Pyrimidines / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Sex Factors

Substances

  • Fungicides, Industrial
  • Pyrimidines
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Oxidoreductases
  • methoxyresorufin-O-demethylase
  • 7-Alkoxycoumarin O-Dealkylase
  • Cytochrome P-450 CYP2E1
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP2B1
  • Aminopyrine N-Demethylase
  • fenarimol