The ability of
metalaxyl, whose mutagenic/cocarcinogenic activity has as yet not been clarified, to affect specific
biomarkers related to non-genotoxic
cocarcinogenesis, was investigated. 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 (200 or 400 mg/kg b.w.) or repeated (200 mg/kg b.w., 3 days) administrations of fungicide. No significant changes in both absolute and relative liver, kidney and lung weights were observed after
metalaxyl treatment. Although a single dose did not significantly affect the considered
monooxygenases, a clear example of selective
CYP3A induction was recorded in different tissues after repeated treatment. A 3 approximately -fold increase in
CYP3A isozymes, probed by N-demethylation of
aminopyrine, was observed in the liver (both sexes). Again, a 5 approximately -fold increase (averaged between male and female) in this
oxidase activity was present in the kidney. No significant change of the selected
biomarkers was observed in the lung. A weak, but significant reduction of
CYP2B1 isoform in liver (male) was also recorded. Liver and kidney
CYP3A overexpression was corroborated by means of Western immunoblotting analysis using rabbit polyclonal
antibodies anti-CYP3A1/2. Northern blotting analysis with
CYP3A cDNA biotinylated probe showed that, in the liver, the expression of this
isozyme is regulated at the
mRNA level. On the whole, these data seem to indicate the cotoxic and cocarcinogenic potential of this fungicide.