Science Inventory

In vitro metabolism of the anti-androgenic fungicide vinclozolin by rat liver microsomes


Sierra-Santoyo, A. S., E. Angeles-soto, M. de Loudes Lopez-Gonzales, R. A. Harrison, AND M. F. HUGHES. In vitro metabolism of the anti-androgenic fungicide vinclozolin by rat liver microsomes. Archives of Toxicology. Springer, New York, NY, 86(3):413-21, (2012).


Studies in the past 10 years have shown the anti-androgenic effects of several pesticides and commercial products. In particular, the fungicide vinclozolin is anti-androgenic. Developing male rats exposed to vinclozolin display signs of feminization. Knowledge about the mechanism of themetabolism of vinclozolin is limited. This study investigated the role of cytochrome P450 in the metabolism of vinclozolin.


Vinclozolin (V) is a fungicide used in agricultural settings. V administered to rats is hydrolyzed to 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (Ml) and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2). V, Ml and M2 have antiandrogenic properties by interacting with the androgen receptor. Data on V, Ml and M2 biotransformation are limited. Our objective was to characterize V metabolism by rat liver microsomes. V was incubated with non-treated adult male Long-Evans rat liver microsomes and NADPH. Several metabolites were detected following extraction of incubate with acetonitrile and analysis by HPLC/DAD/MSD. One metabolite was identified as [3-(3,5-dichlorophenyl)-5-methyl-5-(l,2dihydroxyethyl)- 1 ,3-oxazolid,ine-2,4-dione] (M4), which was gradually converted to 3' ,5'dichloro- 2,3,4-trihydroxy-2-methylbutylanilide (M5). Both co-eluted in the same HPLC peak. Another metabolite ([M7]) was detected by UV but was unstable for mass spectral analysis. The KM app for co-eluted M4/M5 and [M7] were 53.7 and 135.4 f.lM, the Vmax app were 0.812 and 0.669 nmoles/min/mg protein, and CLint were 15.1 and 4.9 ml/min/g protein, respectively. Pilocarpine, orphenadrine and proadifen and anti-rat cytochrome P450 (CYP)2A, 2B and 3Aantibodies inhibited M4/M5 and [M7] formation. These results indicate that V is efficiently metabolized by CYP. Determination of the metabolites of V will provide further insight into the relationship between toxicity and tissue dose of V and its metabolites. .



Record Details:

Product Published Date: 03/01/2012
Record Last Revised: 10/23/2012
OMB Category: Other
Record ID: 239403