BIOMARKERS OF EFFECT IN EVALUATING METALAXYL COCARCINOGENESIS - SELECTIVE INDUCTION OF MURINE CYP 3A ISOFORM

The ability of metalaxyl, whose mutagenic/cocarcinogenic activity has as yet not been clarified, to affect specific biomarkers related to no n-genotoxic cocarcinogenesis, was investigated, Several CYP-dependent reactions have been studied in liver, kidney and lung microsomes deriv ed 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) administ rations of fungicide. No significant changes in both absolute and rela tive liver, kidney and lung weights were observed after metalaxyl trea tment. Although a single dose did not significantly affect the conside red monooxygenases, a clear example of selective CYP3A induction was r ecorded in different tissues after repeated treatment, A 3 similar to -fold increase in CYP3A isozymes, probed by N-demethylation of aminopy rine, was observed in the liver (both sexes), Again, a 5 similar to -f old increase (averaged between male and female) in this oxidase activi ty was present in the kidney. No significant change of the selected bi omarkers was observed in the lung. A weak, but significant reduction o f CYP2B1 isoform in liver (male) was also recorded. Liver and kidney C YP3A overexpression was corroborated by means of Western immunoblottin g analysis using rabbit polyclonal antibodies anti-CYP3A1/2. Northern blotting analysis with CYP3A cDNA biotinylated probe showed that, in t he liver, the expression of this isozyme is regulated at the mRNA leve l, On the whole, these data seem to indicate the cotoxic and cocarcino genic potential of this fungicide.