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 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.
Paolini
M
M
Department of Pharmacology, University of Bologna, Italy.
Mesirca
R
R
Pozzetti
L
L
Sapone
A
A
Cantelli-Forti
G
G
D000409:Alanine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D003043:Cocarcinogenesis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*
D015415:Biomarkers; D005659:Fungicides, Industrial; C028175:metalaxyl; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000409:Alanine