Genetic polymorphisms of GSTT1, GSTM1, GSTP1, MnSOD, and catalase in nonhereditary chronic pancreatitis: evidence of xenobiotic stress and impaired antioxidant capacity.
Epidemiological studies have demonstrated a variety of potential environmental factors that may alter susceptibility to chronic pancreatitis (CP) through oxidative/xenobiotic stress; however, a direct causal and mechanistic role has not been established. We aimed (1) to determine the prevalence of functional genetic polymorphisms in the antioxidant enzymes, glutathione S-transferase GSTM-1, GSTP-1, and GSTT-1, manganese superoxide dismutase, and catalase in CP and (2) to reveal evidence of oxidative stress in patients with CP by measuring whole-blood glutathione redox status. In total, 122 patients with CP (75 alcohol-induced [A1CP], 33 idiopathic [ICP], and 13 hereditary) and 245 age- and sex-matched controls were recruited. The prevalence of the functional GSTT-1 genotype (GSTT-1*A) was significantly higher in CP (88.5%) compared to healthy controls (76%; chi2 = 7.26, P = 0.007). Stratification to disease etiology demonstrated that the GSTT-1*A genotype was also significantly more prevalent among patients with ICP (94%; P = 0.02; 95% CI, 0.04-9.16) but not in those with A1CP. In 22 patients with stable CP, the whole-blood glutathione concentration (median [IQR]: 72 micromol/L [21-181 micromol/L]) and the glutathione redox ratio (GSH/GSSG) (median [IQR]: 9 (3-77]) were significantly reduced compared to those in 20 healthy volunteers (median [IQR]: 815 micromol/L [679-1148 micromol/L], P < 0.001, and 96 [52-347], P = 0.005, respectively). We conclude that the GSTT-1 functional genotype is associated with ICP. Evidence of altered glutathione redox status suggests that this disease modification may be a consequence of oxidative stress or the bioactivation of xenobiotics.
Rahman
Sakhawat Hussain
SH
Academic Unit of Surgery, The General Infirmary, Great George Street, Leeds LS1 3EA, UK. zak-rahman@lineone.net
Nanny
Chaddha
C
Ibrahim
Khadija
K
O'Reilly
Derek
D
Larvin
Michael
M
Kingsnorth
Andrew J
AJ
McMahon
Michael J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002908:Chronic Disease; D003124:Colorimetry; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005978:Glutathione / Q000097:blood; D019803:Glutathione Disulfide / Q000097:blood; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic; D013482:Superoxide Dismutase / Q000235:genetics*
D005978:Glutathione; D019803:Glutathione Disulfide; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D013482:Superoxide Dismutase; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human