Polymorphic expression of the glutathione S-transferase P1 gene and its susceptibility to Barrett's esophagus and esophageal carcinoma.
Factors determining individual susceptibility to esophageal cancer or premalignant Barrett's epithelium are still largely unclear. An imbalance between phase I drug metabolism [e.g., cytochrome P450 (CYP)] and phase II detoxification [e.g., glutathione S-transferase (GST)] may contribute to the development of these diseases. Polymorphic variants in the CYP1A1 gene were described leading to increased levels of bioactive compounds, whereas polymorphisms in GST genes often resulted in impaired detoxification. We studied the frequencies of polymorphic variants in CYP1A1, GSTP1, GSTT1, and GSTM1 genes in 98 patients with Barrett's epithelium and 34 patients with esophageal cancer. The results were compared with those obtained from 247 healthy blood donors. DNA was extracted, and PCR-RFLP methods were used to detect genetic polymorphisms. Chi2 analysis, Spearman rank correlation, and Wilcoxon rank sum tests were used for statistical evaluation. Polymorphisms in CYP1A1, GSTM1, and GSTT1 occurred at an equal frequency in patients and controls. Occurrence of the polymorphic GSTP1b variant in the GSTP1 gene resulted in a significantly lower GST enzyme activity (P < 0.05), and GSTP1b was found significantly more often in patients with Barrett's epithelium (70%; P < 0.001) and patients with esophageal adenocarcinoma (76%; P = 0.005), as compared to healthy blood donors (41%). In conclusion, presence of the GSTP1b allele leads to lower GST enzyme activity levels and, consequently, impaired detoxification. This most important esophageal GST isoform may, therefore, contribute to the development of Barrett's epithelium and adenocarcinoma.
van Lieshout
E M
EM
Department of Gastroenterology, University Hospital St. Radboud, Nijmegen, The Netherlands.
Roelofs
H M
HM
Dekker
S
S
Mulder
C J
CJ
Wobbes
T
T
Jansen
J B
JB
Peters
W H
WH
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000201:enzymology* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic