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Biomarkers of effect in evaluating dithianon cocarcinogenesis: selective induction and suppression of murine CYP3A
M Paolini1, R Mesirca, L Pozzetti
1Department of Pharmacology, University of Bologna, Italy. paolini@biocfarm.unibo.it
Abstract:
The ability of dithianon, whose mutagenic/cocarcinogenic activity has as yet not been clarified, to affect specific biomarkers of effect related to non-genotoxic cocarcinogenesis was investigated. For this purpose, several CYP-dependent reactions have been studied in liver, kidney and lung microsomes derived from male and female Swiss Albino CD1 mice treated i.p. with single (3 or 6 mg kg(-1) b.w.) or repeated (3 mg kg(-1) b.w., daily for 3 days) administrations of such fungicide. No significant changes in both absolute and relative liver, kidney and lung weights were achieved after dithianon treatment. Whereas a single dose was able to significantly induce certain monooxygenases, with repeated treatments a loss of activity was observed. For example, a approximately 2.4-fold increase of CYP3A-dependent activity, probed by N-demethylation of aminopyrine, was achieved in the liver (both sexes, lower dose) and, to a lesser extent, in lung. A small, but significant increase in the hydroxylation of p-nitrophenol (2E1) and in the O-deethylation of ethoxycoumarin (mixed) was also found in liver. With the exception of a approximately 46% loss in the 3A-like activity, no appreciable changes of the selected biomarkers were observed in kidney. Repeated dithianon doses were able to significantly reduce the 3A- and 2E1-dependent monooxygenases (approximately 30% and approximately 30% loss, respectively, averaged between male and female), as well as ethoxycoumarin O-deethylase activity (approximately 54% loss) in the liver. On the contrary, no significant CYP modulation in both kidney and lung was recorded. On the whole, dithianon has a complex pattern of CYP induction or suppression in various tissues of both sexes, suggesting the possible toxic/cotoxic and cocarcinogenic potential of this fungicide. These data can contribute to a better understanding of its toxicological profile, providing more information concerning the risk associated to human exposure.
Insights
Dithianon fungicide alters liver enzyme activity in mice, showing induction after a single dose and suppression after repeated doses, suggesting potential toxic and cocarcinogenic effects.
Area of Science:
- Toxicology
- Biochemistry
- Environmental Health
Background:
- The mutagenic and cocarcinogenic potential of dithianon, a widely used fungicide, remains unclear.
- Understanding its effects on specific biomarkers is crucial for assessing non-genotoxic cocarcinogenesis risks.
Purpose of the Study:
- To investigate the impact of dithianon on cytochrome P450 (CYP)-dependent enzyme activities in mice.
- To evaluate dithianon's potential toxic, cotoxic, and cocarcinogenic effects based on biomarker responses.
Main Methods:
- Swiss Albino CD1 mice (male and female) were administered single or repeated doses of dithianon.
- Liver, kidney, and lung microsomes were analyzed for changes in CYP-dependent enzyme activities.
- Specific reactions like aminopyrine N-demethylation, p-nitrophenol hydroxylation, and ethoxycoumarin O-deethylation were measured.
Main Results:
- Single dithianon doses induced certain CYP enzymes in the liver and lung, notably CYP3A and 2E1.
- Repeated dithianon administration led to significant suppression of CYP3A, 2E1, and ethoxycoumarin O-deethylase activities in the liver.
- Kidney and lung tissues showed minimal changes in CYP activity, except for a partial loss of 3A-like activity in the kidney.
Conclusions:
- Dithianon exhibits a complex pattern of CYP enzyme induction and suppression across different tissues and sexes.
- These findings suggest a potential toxic, cotoxic, and cocarcinogenic role for dithianon.
- Further research is needed to fully elucidate the toxicological profile and human exposure risks associated with dithianon.