The genetic and non-genetic toxicity of the fungicide Vinclozolin.
The mutagenic/cocarcinogenic potential of the fungicide Vinclozolin was assessed by a comprehensive examination of toxicity mechanisms at both the genetic and the metabolic level. Vinclozolin did not induce any significant increase in chromosomal aberrations in human pheripheral blood lymphocytes cultured in vitro, both in the presence and in the absence of metabolic activation. However, significant dose-related increases in micronucleated erythrocytes (up to 4-fold over the control) were found in the bone marrow cells of mice 24 h after treatment with the fungicide over a range of concentrations from 312.5 to 1250 mg/kg. The morphology and the size of micronuclei induced was suggestive of a predominantly clastogenic mode of action. Several cytochrome P450 (CYP)-dependent reactions have been monitored in liver, kidney and lung microsomes of male and female Swiss Albino CD1 mice in order to ascertain certain toxic non-genetic properties (related to carcinogenesis) of Vinclozolin. It was found to be a selective inducer towards CYP 3A (liver, kidney) and 2E1 (liver), as exemplified by the significant increases of the demethylation of aminopyrine (APND, up to 2.3-fold, female liver), and hydroxylation of p-nitrophenol (pNPH, up to 5.6-fold, male liver). In general, however, Vinclozolin has a complex pattern of induction and suppression of CYP-dependent enzymes, as shown from the reduced expression of various monooxygenases depending upon dose, sex or organ considered. For example, pNPH activity was suppressed in kidney (up to 48% loss, averaged between male and female), whereas ethoxycoumarin O-deethylase was reduced in lung up to 53% in male (at the highest dose). These data were sustained by means of Western immunoblotting using rabbit polyclonal antibodies anti-CYP 3A and 2E1. Northern blotting analysis using CYP 3A1/2 and 2E1 cDNA biotinylated probes showed that the expression of such isozymes is regulated at the mRNA level. Taken together, the findings indicate the clastogenic activity and the possible cotoxic, cocarcinogenic and promoting potential of Vinclozolin.
Hrelia
P
P
Department of Pharmacology, University of Bologna, Italy.
Fimognari
C
C
Maffei
F
F
Vigagni
F
F
Mesirca
R
R
Pozzetti
L
L
Paolini
M
M
Cantelli Forti
G
G
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D002869:Chromosome Aberrations; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009153:Mutagens / Q000633:toxicity*; D010080:Oxazoles / Q000633:toxicity*; D011817:Rabbits
D002273:Carcinogens; D005659:Fungicides, Industrial; D009153:Mutagens; D010080:Oxazoles; D003577:Cytochrome P-450 Enzyme System; C025643:vinclozolin