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Examination of a CYP2E1 repeat polymorphism in a monkey model of alcohol abuse
S J Walker1, K A Grant, K E Vrana
1Center for the Neurobehavioral Study of Alcohol, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27156, USA. swalker@wfubmc.edu
Background:
Cytochrome P-450 2E1 (CYP2E1) is involved in alcohol metabolism, and the expression of this enzyme displays wide phenotypic variability in humans. It has been proposed that some of this variability in expression may be a consequence of the size of a repeat polymorphism in the 5" regulatory region of the gene and that the polymorphism may segregate with alcoholism. This study examined whether the repeat polymorphism exists in macaque monkeys and whether it associates with excessive alcohol consumption in this animal model.
Methods:
Ten outbred cynomolgus monkeys (Macaca fascicularis) that displayed a voluntary alcohol consumption ranging from 1.0 to 3.6 g/kg/day were genotyped for a CYP2E1 repeat polymorphism. This polymorphism has been documented in the region from -2519 base pair (bp) to -1953 bp of the human CYP2E1 gene 5" distal promoter.
Results:
Individual polymerase chain reaction amplification of genomic DNA from each of the 10 monkey samples revealed a single band of approximately 400 bp in the region corresponding to the human CYP2E1 polymorphism. Polymerase chain reaction amplicons from the 10 individuals were sequenced, and each one generated a 370 bp sequence that is 90% identical to the human gene sequence. However, unlike human alleles that contain five to eight repeats, the cynomolgus monkey is homozygous for a single copy of the repeat most closely resembling repeat 8 (88% identical) in the human gene.
Conclusions:
These data demonstrate that the CYP2E1 distal promoter region in monkeys is very similar to the human sequence yet lacks the extensive repeated DNA found in humans. This includes the rare repeats 3 and 4, which have been postulated to play a role in transcription regulation and to associate with alcohol abuse liability in humans. These data suggest that the CYP2E1 polymorphism arose late in evolution and that the regulation of the gene by this genetic region is not associated with a heavy alcohol drinking phenotype in the cynomolgus monkey.
