GENETIC AND NONGENETIC 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 asse ssed in human peripheral blood lymphocytes in vitro, while the inducti on of micronuclei was studied in male CD1 mouse bone marrow polychroma tic erythrocytes (PCE). Fenarimol did not induce any significant incre ase in chromosomal aberrations in vitro, either in the presence or abs ence of rat liver S9 fraction. In contrast, a 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 c ontrary, CYP 3A, probed by N-demethylation of aminopyrine, were only i nduced in the liver, Results were corroborated by means of Western imm unoblotting using rabbit polyclonal antibodies anti-CYP 2B1 and 3A. No rthern 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) cotox ic/cocarcinogenic and promoting potential of this fungicide.