Genetic and non-genetic biomarkers related to carcinogenesis in evaluating toxicological risk from Fenarimol.
A multibiomarker approach based on the study of toxicity mechanisms at both genetic and metabolic levels has been applied to Fenarimol. With regard to genotoxicity, particular attention was given to assays for chromosomal aberration and micronuclei; clastogenic potential was assessed in human peripheral blood lymphocytes in vitro, while the induction of micronuclei was studied in male CD1 mouse bone marrow polychromatic erythrocytes (PCE). Fenarimol did not induce any significant dose-related increase in micronucleated PCEs, up to 4-fold above the control level at a single dose of 75 mg/kg b.w., was observed 24 h after treatment. Using selective biochemical markers of effect Fenarimol was found to induce CYP 2B1 isoforms in liver, kidney and lung microsomes of Swiss Albino CD1 male and female mice, as shown by the significant increase in specific 2B1-probe pentoxyresorufin O-dealkylase activity. On the contrary, CYP 3A, probed by N-demethylation of aminopyrine, were only induced in the liver. Results were corroborated by means of Western immunoblotting using rabbit polyclonal antibodies anti-CYP 2B1 and 3A. Northern blotting analysis with CYP 2B1 and 3A cDNA biotinylated probes showed that the expression of such isoforms is regulated at mRNA level. Taken as a whole, these data indicate the possible (mutagenic) cotoxic/cocarcinogenic and promoting potential of this fungicide.
Paolini
M
M
Department of Pharmacology, Biochemical, University of Bologna, Italy.
Mesirca
R
R
Pozzetti
L
L
Maffei
F
F
Vigagni
F
F
Hrelia
P
P
Cantelli-Forti
G
G
D000818:Animals; D015415:Biomarkers; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002869:Chromosome Aberrations; D003580:Cytochromes / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D005819:Genetic Markers; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D011743:Pyrimidines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats
D015415:Biomarkers; D002273:Carcinogens; D003580:Cytochromes; D005659:Fungicides, Industrial; D005819:Genetic Markers; D007527:Isoenzymes; D011743:Pyrimidines; C033789:fenarimol