The glutathione S-transferase mu polymorphism as a marker for susceptibility to lung carcinoma.

Glutathione S-transferase (GST) enzymes detoxify carcinogens in tobacco smoke. Interindividual variation in GST function may be related to differences in risk for smoking-related cancer. Leukocytes from 50% of Caucasians lack GST activity toward trans-stilbene oxide (TSO), due to a deletion of the gene for the GST-mu enzyme. Presence of GST-TSO activity in leukocytes has been associated with low risk for lung cancer among cigarette smokers. We sought to determine whether GST activity in lung tissue is determined by the same gene polymorphism and whether it is associated with risk for lung cancer. Subjects were cigarette smokers, identified at the time of lung resection or autopsy in Seattle hospitals. Uninvolved lung tissue was obtained from 35 patients with lung carcinoma and 43 control patients and assayed for GST-mu activity with TSO, for the presence of the GST-mu gene product with an immunological assay, and for the GST-mu gene with Southern blotting. Mailed questionnaires were used to collect information on subjects' smoking histories and exposures which might alter enzyme activity. Interindividual results from the three assays correlated well. Smokers with high GST-TSO enzyme activity present in their lung tissue had a lower risk for lung carcinoma than did smokers with no or low activity (relative risk = 0.30; 95% confidence interval, 0.11-0.79), as did smokers with GST-mu antigen identified in lung tissue versus those with no antigen (relative risk = 0.30; 95% confidence interval, 0.11-0.79). Smokers with both maternal and paternal copies of GST-mu DNA (n = 7) had a lower cancer risk than smokers lacking GST-mu DNA (n = 30; relative risk = 0.35; 95% confidence interval, 0.06-2.10). High GST-mu activity appeared to be associated with a greater decrease in lung cancer risk among 38 heavy cigarette smokers (relative risk = 0.15; 95% confidence interval, 0.03-0.64) than among 38 light smokers (relative risk = 0.61; 95% confidence interval, 0.14-2.60). Presence or absence and number of copies of the GST-mu gene appear to determine activity of the GST-mu enzyme in lung. Smokers with the GST-mu enzyme have approximately one-third of the risk for lung carcinoma of smokers without the enzyme.

Glutathione S-transferase and epoxide hydrolase activity in human leukocytes in relation to risk of lung cancer and other smoking-related cancers.

BACKGROUND: There is considerable interindividual variation in the activity of enzymes which metabolize polycyclic aromatic hydrocarbon constituents of tobacco smoke. Low activity of enzymes which detoxify carcinogenic polycyclic aromatic hydrocarbon metabolites may be associated with increased susceptibility to cancers etiologically related to cigarette smoking. PURPOSE: We conducted a population-based, case-control study to determine whether patients with cancers related to smoking had lower activity of detoxifying isoenzymes of glutathione S-transferase (GST) and epoxide hydrolase (EH) than control subjects. METHODS: Enzyme activities were measured in leukocytes from 113 King County (Washington) residents diagnosed during 1987 with one of three smoking-related cancers (lung, oropharynx/oral cavity, or bladder), 50 King County residents with cancers believed unrelated to smoking (prostate cancer or non-Hodgkin's lymphoma), and 120 persons selected at random from the King County population. Enzyme activity measurements were made for leukocyte cytosolic GST toward transstilbene oxide (TSO), 1-chloro-2,4-dinitrobenzene, and benzo[a]pyrene-4,5-oxide (BaPO), and for microsomal EH toward BaPO. RESULTS: Overall, the distribution of activity levels of GST toward TSO and BaPO did not differ in case patients with smoking-related cancer compared with control subjects. The activities of GST toward 1-chloro-2,4-dinitrobenzene and of EH toward BaPO were somewhat lower on average in case patients with smoking-related cancers than in control subjects, but these differences were well within the limits of chance. Among the heaviest smokers, there were proportionately fewer patients with smoking-related cancers than control subjects with intermediate or high GST activity toward TSO (odds ratio = 0.6), but this difference was also plausibly due to chance (95% confidence interval = 0.3-1.1). CONCLUSIONS: While the findings of this study are compatible with a moderate protective effect of high or intermediate enzyme activity among persons heavily exposed to tobacco, as suggested by an earlier report, the data are by no means conclusive.

Paraoxon hydrolysis in human serum mediated by a genetically variable arylesterase and albumin.

Gel filtration chromatography resolves human serum paraoxonase into two fractions: (1) a high molecular weight fraction that is completely inhibited by EDTA and coelutes with arylesterase (E.C.3.1.1.2); and (2) a second fraction that is closely associated with albumin, is only partially inhibited by EDTA, and has relatively little arylesterase activity under the assay conditions used. The activity of the high molecular weight fraction is stimulated by NaCl, whereas the albumin associated activity is partially inhibited by NaCl and is not present in serum derived from an analbuminemic individual. Our data suggest that albumin itself, rather than a protein bound to or cofractionating with albumin, mediates paraoxonase activity. The variation in levels of the activity of the nonalbumin, high molecular weight enzyme is responsible for the observed polymorphism of paraoxonase activity in human serum or plasma. An optimal assay of polymorphic paraoxonase activity should be based on activity measurements of the nonalbumin fraction. It is considered likely that only the nonalbumin fraction is responsible for in vivo hydrolysis of paraoxon.

Effect of chronologic age on induction of cystathionine synthase, uroporphyrinogen I synthase, and glucose-6-phosphate dehydrogenase activities in lymphocytes.

The activities of cystathionine synthase [L-serine hydro-lyase (adding homocysteine), EC 4.2.1.22], uroporphyrinogen I synthase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8], and glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate:NADP+ 1-oxidoreductase, EC 1.1.1.49) have been measured in phytohemagglutinin-stimulated lymphocytes of young and old human subjects. A significant decrease in activity with age was observed for cystathionine synthase and uroporphyrinogen I synthase but not for glucose-6-phosphate dehydrogenase. These changes could not be related to declining phytohemagglutinin response with aging. Age-related decreases in activity of some enzymes may be relevant for an understanding of the biology of aging. False assignment of heterozygosity, and even homozygosity, for certain genetic disorders, such as homocystinuria, may result when low enzyme levels are detected in the lymphocytes of older people.