Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Although cytosolic glutathione S-transterase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes. GST1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GsTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals. e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence Suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestivc tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Social inequalities in male mortality, and in male mortality from smoking: indirect estimation from national death rates in England and Wales, Poland, and North America

Background There are substantial social inequalities in adult male mortality in many countries. Smoking is often more prevalent among men of lower social class, education, or income. The contribution of smoking to these social inequalities in mortality remains uncertain. Methods The contribution of smoking to adult mortality in a population can be estimated indirectly from disease-specific death rates in that population (using absolute lung cancer rates to indicate proportions due to smoking of mortality from certain other diseases). We applied these methods to 1996 death rates at ages 35-69 years in men in three different social strata in four countries, based on a total of 0.6 million deaths. The highest and lowest social strata were based on social class (professional vs unskilled manual) in England and Wales, neighbourhood income (top vs bottom quintile) in urban Canada, and completed years of education (more than vs less than 12 years) in the USA and Poland. Results In each country, there was about a two-fold difference between the highest and the lowest social strata in overall risks of dying among men aged 35-69 years (England and Wales 21% vs 43%, USA 20% vs 37%, Canada 21% vs 34%, Poland 26% vs 50%: four-country mean 22% vs 41%, four-country mean absolute difference 19%). More than half of this difference in mortality between the top and bottom social strata involved differences in risks of being killed at age 35-69 years by smoking (England and Wales 4% vs 19%, USA 4% vs 15%, Canada 6% vs 13%, Poland 5% vs 22%: four-country mean 5% vs 17%, four-country mean absolute difference 12%). Smoking-attributed mortality accounted for nearly half of total male mortality in the lowest social stratum of each country. Conclusion In these populations, most, but not all, of the substantial social inequalities in adult male mortality during the 1990s were due to the effects of smoking. Widespread cessation of smoking could eventually halve the absolute differences between these social strata in the risk of premature death.

Concentration dependent effects of N1,N11-diethylnorspermine on melanoma cell proliferation

N-1, N-11-Diethylnorspermine (DENSPM) is a polyamine analog that is currently under investigation as a novel anticancer drug. Although it has shown promising preclinical activity, there has been large variation in responsiveness reported between different human cancers. During our studies into the causes of this variation, we observed a consistent increase in cell proliferation at low drug concentrations (

The PCNA-associated factor KIAA0101/p15(PAF) binds the potential tumor suppressor product p33ING1b

The KIAA0101/p15(PAF)/OEATC-1 protein was initially isolated in a yeast two-hybrid screen for proliferating cell nuclear antigen (PCNA) binding partners, and was shown to bind PCNA competitively with the cell cycle regulator p21(WAF). PCNA is involved in DNA replication and damage repair. Using polyclonal antisera raised against a p15(PAF) fusion protein, we have shown that in a range of mammalian tumor and non-tumor cell lines the endogenous p15(PAF) protein localises to the nucleus and the mitochondria. Under normal conditions no co-localisation with PCNA could be detected, however following exposure to UV it was possible to co-immunoprecipitate p15(PAF) and PCNA from a number of cell lines, suggesting a UV-enhanced association of the two proteins. Overexpression of p15(PAF) in mammalian cells was also found to protect cells from UV-induced cell death. Based on similarities between the behaviour of p15(PAF) and the potential tumor suppressor product p33ING1b, we have further shown that these two proteins interact in the same complex in cell cultures. This suggests that p15(PAF) forms part of a larger protein complex potentially involved in the regulation of DNA repair, apoptosis and cell cycle progression. (c) 2005 Elsevier Inc. All rights reserved.

Association between glutathione S-transferase M1 and T1 and the risk for coronary heart disease (CHD)

Deficiency of Glutathione S-transferases (GST) M1 and T1 are associated with chronic diseases (e.g. lung cancer, MS) and could be one factor for the risk for CHD.We conducted a pros-pective case-control study in 93 pts. with angiographically proven CHD and 161 controls matched for age ±2y and gender (resulting in n=91 pairs, of which 18 were female). Genes coding for functional GST M1 and T1 were analysed acoording to previously published methods. The association between GST M1, T1 was tested using Fisher's exact test; logistic regression analysis was performed to control for HDL-cholesterol, diabetes smoking, diabetes, hypertension. 41% of cases were smokers, 25% had diabetes and 68% hypertension, corresponding figures for controls were 31%, 13% and 33%. Mean HDL-cholesterol levels were comparable (pts: 46±14 mg/dl, controls: 43± 19 mg/dl). There was no overall significant correlation between functional GST T1 and M1 genotypes and CHD, however, there seems to be an association between GST M1, HDL-cholesterol and CHD. Larger studies are needed to verify these data.

Can physical activity prevent diabetes?

Most physical activity researchers are familiar with the epidemiological evidence that suggests that physical activity has an important role in the primary prevention of Type 2 diabetes. There is compelling evidence from large well-conducted prospective cohort trials to show that the risk of diabetes is reduced by up to 50% in people who are habitually active. There is also evidence from large randomised controlled trails to support the view that physical activity, as part of a lifestyle change program, can prevent Type 2 diabetes and the onset and progression of metabolic syndrome. This is the strongest evidence in support of a beneficial role for physical activity in the primary prevention of any health problem; much stronger than that for the links between smoking and lung cancer. This presentation will critically evaluate this evidence, and explore the notion that, while physical activity may postpone the development of Type 2 diabetes, it may not actually prevent the onset of problem at the population level. As the (self-reported) prevalence of Type 2 diabetes has more than doubled in the last 20 years, it is critical that we explore effective strategies for ensuring that we can ‘activate’ Australians sufficiently to prevent, rather than simply postpone, the development of this significant health problem.