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Testosterone hydroxylase in evaluating induction and suppression of murine CYP isoenzymes by fenarimol
M Paolini1, L Pozzetti, R Mesirca
1Department of Pharmacology, University of Bologna, Italy.
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.
Insights
Fenarimol significantly alters drug metabolism in mice, affecting liver, kidney, and lung enzymes. This fungicide
Area of Science:
- Toxicology
- Pharmacology
- Drug Metabolism
Background:
- Cytochrome P450 (CYP) enzymes are crucial for drug metabolism and detoxification.
- Fungicides can interfere with these enzymatic pathways, potentially leading to adverse health effects.
- Understanding fenarimol's impact on CYP activity is essential for assessing its toxicological profile.
Purpose of the Study:
- To investigate the effects of single and repeated fenarimol administration on murine liver, kidney, and lung microsomal CYP-catalyzed drug metabolism.
- To evaluate the modulation of testosterone hydroxylation by fenarimol.
- To assess the potential toxic, cotoxic, and cocarcinogenic properties of fenarimol.
Main Methods:
- Murine models (male and female mice) were used.
- Fenarimol was administered as a single dose or repeated doses.
- Microsomal CYP-catalyzed testosterone hydroxylation activities were measured in liver, kidney, and lung tissues.
- Specific CYP isoforms and their activities were analyzed.
Main Results:
- Fenarimol induced or suppressed various CYP activities in a dose- and sex-dependent manner.
- In liver, single doses of fenarimol induced 7 alpha-testosterone hydroxylase (TH) activity up to 4.8-fold in females, while reducing other TH activities.
- Repeated fenarimol treatment markedly induced all steroid hydroxylations, with up to 78-fold induction of 2 alpha-TH activity in male liver.
Conclusions:
- Fenarimol exhibits a complex pattern of CYP induction and suppression across different tissues and sexes.
- These modulations suggest potential toxic, cotoxic, and cocarcinogenic effects of fenarimol.
- Further research is warranted to fully elucidate the risks associated with fenarimol exposure.