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Vol. 28, Issue 8, 981-986, August 2000

Cloning of Canine Cytochrome P450 2E1 cDNA: Identification and Characterization of Two Variant Alleles1

Susan M. Lankford, Stephen A. Bai, and Joyce A. Goldstein

Department of Anatomy, Physiological Sciences and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina (S.M.L.); DuPont Pharmaceuticals Company, Newark, Delaware (S.A.B.); and National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (J.A.G.)

Cytochrome P450 (CYP) 2E1 is a toxicologically important enzyme that inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms. Although cDNAs for the human, rodent, and rabbit forms of CYP2E1 have been isolated and studied extensively, there is an absence of information about canine CYP2E1, despite the fact that the dog is routinely used in drug safety studies. In this study, we isolated and sequenced a full-length CYP2E1 cDNA from a beagle liver cDNA library. The deduced canine CYP2E1 amino acid sequence exhibited 75 to 76% identity with rat, mouse, and rabbit CYP2E1 sequences, and 77% identity with human CYP2E1. Two populations of clones, differing at a single nucleotide, were isolated from the unamplified library. The T1453C base change results in a Tyr485His amino acid substitution, which is well beyond the heme binding region but is possibly part of a beta -sheet structure. An allele-specific polymerase chain reaction-based restriction enzyme test was developed for genotyping individual dogs from genomic DNA samples. One hundred mixed breed dogs were genotyped, and the frequencies of the Tyr485 and His485 alleles were found to be 0.85 and 0.15, respectively. The canine Tyr485 and His485 alleles and human CYP2E1 were expressed in Escherichia coli cells, and catalytic activities of the proteins were assessed using the substrate chlorzoxazone. Although the two canine enzymes had similar catalytic activity; significant kinetic differences were seen between canine and human CYP2E1s.

1 The nucleic acid sequences in this paper have been submitted to GenBank under accession numbers AFO29978 and AFO29979.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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