Characterization of a unique aldo-keto reductase responsible for the reduction of chlordecone in the liver of the gerbil and man.
It has been established that the major metabolic pathway for chlordecone (CD) (Kepone) both in humans and in the Mongolian gerbil is bioreduction of this organochlorine pesticide to chlordecone alcohol (CDOH) in the liver. In the present study we developed a gas-liquid chromatography assay to measure the enzymatic reduction of CD to CDOH in vitro and characterized "CD reductase" activity in gerbil liver cytosol. CD reductase is a cytosolic enzyme readily detectable in liver samples prepared from humans, rabbits, and gerbils, the only species of many tested that convert CD to CDOH in vivo. Gerbil CD reductase exhibited a Km of 2.6 microM, a Vmax of 0.14 nmol/min, and a pH optimum of 6.5. The enzyme activity required NADPH, was sensitive to thiol reagents, and was distributed in all tissues with the highest activities found in the liver, intestine, and kidneys. These results are consistent with CD reductase belonging to the family of enzymes referred to as the "aldo-keto reductases." However, unlike previously described reductases, CD reductase was undetectable in rats, mice, hamsters, or guinea pigs and was insensitive to the model aldehyde and ketone reductase inhibitors, phenobarbital and quercetin, respectively. In addition, CD reductase activity in liver was increased by 38% (p less than 0.01) following treatment of gerbils with CD. We conclude that CD reductase is a novel aldo-keto reductase that is uniquely inducible by its substrate.
Molowa
D T
DT
Wrighton
S A
SA
Blanke
R V
RV
Guzelian
P S
PS
D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D007631:Chlordecone / Q000031:analogs & derivatives / Q000378:metabolism*; D006224:Cricetinae; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D064430:NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014018:Tissue Distribution
D007306:Insecticides; C029713:chlordecone alcohol; D000429:Alcohol Oxidoreductases; D064430:NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; C048321:chlordecone reductase; D007631:Chlordecone