Chlordecone alcohol formation in the Mongolian gerbil (Meriones unguiculatus): a model for human metabolism of chlordecone (kepone)

Abstract

In seeking a practical animal model of chlordecone metabolism in humans, we found that among rats, hamsters, guinea pigs, or gerbils treated with a single injection of chlordecone, only in gerbils was this organo-chlorine pesticide converted to chlordecone alcohol, a reduced metabolite found in the stool of chlordecone poisoned humans. Analogous to these patients, chlordecone treated gerbils eliminated chlordecone alcohol exclusively in stool with none being detected in urine. Moreover, the gerbils excreted chlordecone alcohol in bile in an amount more than twice that of chlordecone and in the form of a glucuronide conjugate. The ratio of chlordecone to chlordecone alcohol in gerbil stool was 10 times higher than the ratio in human stool. This suggests that the newly recognized nonbiliary mechanism(s) for entry of chlordecone into the intestinal lumen (Boylan et al., Clin. Pharm. Ther. 25:579-585, 1979) may be extremely active in the gerbil. Biliary excretion of chlordecone alcohol in gerbils progressively increased following chlordecone treatment while biliary excretion of chlordecone remained unchanged. Incubation of the cytosolic fraction of gerbil liver homogenate in the presence of NADPH and chlordecone produced chlordecone alcohol, whereas rat liver cytosol was inactive. This observation indicates that bioreduction of chlordecone is catalyzed in gerbil liver by a species-specific reductase. Rats given [3H]-chlordecone alcohol excreted twice as much (80%) of the compound in stool after three days as compared to gerbils (40%), while the latter species accumulated three times more chlordecone alcohol in the liver than did the former. An unexpected finding was that the livers of these [3H]-chlordecone alcohol treated animals also contained chlordecone in amounts eight times (rat) and 14 times (gerbil) higher than the respective amounts of chlordecone alcohol. From this result, the existence of a separate enzyme(s) catalyzing dehydrogenation of chlordecone alcohol to chlordecone may be inferred.