CHLOROTHALONIL BIOTRANSFORMATION BY GASTROINTESTINAL MICROFLORA - IN-VITRO COMPARATIVE APPROACH IN RAT, DOG, AND HUMAN

Chlorothalonil (2,4,5,6-tetrachloroisophthalonitrile) is a broad spect rum contact fungicide used in agriculture and horticulture. The role o f digestive microflora in chlorothalonil metabolism was assessed by in vitro incubation of [C-14]chlorothalonil with stomach, duodenum, and cecum contents from rat, stomach, duodenum, and colon contents from do g and with human frees and stomach contents using an incubation dose o f 500 mu g/g of digestive contents. Transformation of chlorothalonil m ostly occurred in rat cecum contents, dog colon contents, and human fe ces, in which unchanged chlorothalonil accounted for 46.7, 29.7, and 2 2.6% of the radioactivity, respectively. In those incubations, the ide ntified metabolites were: 2,5,6-trichloro-4-methylthioisophthalonitril e (0.8-3% of the radioactivity), 2,5,6-trichloro-3-thioisophthalonitri le (0-7.1%), 3-thia-1-cyano-2,5,6-trichloroisoindolinone (2.6-12.7%), 2,5,6-trichloro-4-hydroxy-isophthalonitrile (0-3.2%), and 2,5,6-trichl oroisophthalonitrile (9.9-21.4%). The mercapto metabolites of chloroth alonil, methylated or not, were recovered from rat and dog duodenum co ntents (0.8 and 0.7%). Only traces of metabolic products were recovere d from rat and human stomach contents. The monocysteine conjugate of c hlorothalonil was detected from rat duodenum contents and accounted fo r 0.2% of the substrate. The formation of metabolites decreased when t he digestive contents were heated before incubation to inactivate bact eria. Under these conditions. the monomethylthiotrichloroisophthalonit rile formation was suppressed, except in rat and dog duodenum contents (1.5 and 0.5%, respectively). The monothiotrichloroisophthalonitrile accounted for 0.1 to 0.4%. The monohydroxytrichloroisophthalonitrile a ccounted for 0.5 to 2%, the thiaindolinone metabolite for 3.9 to 8% an d the dechlorinated chlorothalonil for 0.3 to 2.8%. These results sugg est that intestinal microflora plays a significant role in chlorothalo nil metabolism which implies Cys beta-lyases. The formation of methylt hio metabolites is discussed, including thiol methylation in digestive contents. (C) 1997 Academic Press.