Genetic polymorphisms of the cytochrome P450 2C xenobiotic metabolising enzymes subfamily and predisposition to adenomatous polyps of the colon and rectum

Abstract

To study cytochrome P4502C subfamily gene polymorphisms in the polyp and non-polyp population of the Imperial Cancer Research Fund flexible sigmoidoscopy screening trial and establish any association with adenomatous polyps of the colon. 

The vast majority of environmental compounds are inert requiring activation to become carcinogens by xenobiotic metabolising enzymes.  Individuals exhibiting different expression patterns of these enzymes, possibly due to generic polymorphisms, vary in their susceptibility to the effects of environmental factors.  The CYP2C subfamily enzymes are known to be involved in the metabolism of several commonly used drugs, notably, omeprazole, warfarin, non-steroidal anti-inflammatories, tolbutamide & diazepam, as well as a number of environmental mutagens such as benz[a]pyrene (3)

DNA based polymerase chain reaction and restriction fragment length polymorphism methods were used to determine the frequency of CYP2C8, 9, 18 and 19 polymorphisms (Table 17) in individuals attending the ICRF screening trail.

For CYP2C8 there is a reported base pair change a to c at position 390.  The c base is the wild type (WT) and an allele is very rare and may not exist at all.  For CYP2C18 a reported t to c base pair change at position 1154 did not appear to exist.  Allele frequencies in a UK population for CYP2C9, CYP2C18 and CYP2C19 polymorphisms have been established.  There was no statistically significant difference for any of the polymorphisms studied between those with adenomas and controls.  There were more heterozygotes and homozygotes combined in the adenoma group for the polymorphism termed CYP2C9.  This did not reach significance (p=0.064).  There is evidence that this polymorphism has a dominant effect and is involved in benz[a]pyrene metabolism, a smoking carcinogen.  Smoking has been shown to predispose to colorectal adenomas.

None of the CYP2C subfamily polymorphism studied were shown to predispose to adenomatous polyps of the distal colon and rectum.  CYP2C9 warrants further investigation.

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