Enantiospecific Disposition of Chlordane in a Mouse Model Lacking NADPH-Dependent Cytochrome 450 Reductase

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Project Period: 
2011
Project Investigator(s): 
E.D. Oldham, I. Kania-Korwel, H.J. Lehmler, Department of Occupational and Environmental Health, University of Iowa
Abstract: 

The  pesticide  chlordane  is  a  mixture  of  structurally  related,  highly chlorinated hydrocarbons and is a persistent environmental contaminant linked to a range of adverse health effects in animals. Most of the isomers are chiral, and may be metabolized in an enantiospecific manner. This type of metabolism has been shown for other chiral pollutants. We hypothesize that chiral chlordane isomers are metabolized enantioselectively by cytochrome P450 enzymes. To test this hypothesis we will take advantage of  a knockout mouse model lacking the  NADPH-dependent cytochrome P450 reductase, a critical enzyme in the catalytic cycle of P450 oxidation, and measure levels and enantiomeric fractions of chlordane and its metabolites in tissue from wild- type and knockout mice. This research will provide key mechanistic information about enantiospecific metabolism of chlordane, and can be extended to other pesticides commonly found in Iowa.

Publications: 

Kania-Korwel I, Lehmler HJ. Chlordane and heptachlor are metabolized enantioselectively by rat liver microsomes. Environ Sci Technol 2013; 47:8913-8922.

Wu X, Barnhart C, Lein PJ Lehmler HJ. Hepatic metabolism affects the atropselective disposition of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice. Environ Sci Technol 2015; 49:616-625.