Smoking, genetic polymorphisms of glutathione S-transferases and biological indices of inflammation and cellular adhesion in the STANISLAS study

A recent clinical study has focused on: 1- the interaction between genetic variants of glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) and smoking on the risk of cardiovascular diseases, 2- the potential capacity of GSTM1 and T1 genotypes in modifying the effect of smoking on inflammation and endothelial function. In this study, we investigated whether carriage of these 2 polymorphisms altered the smoking impact on biological indices of inflammation and cellular adhesion. White blood cell count (WBC), albumin, C-reactive protein (CRP), interleukine-6 (IL-6), tumor necrosis factor-alpha (TNF-a), L-selectin, E-selectin, P-selectin and intracellular adhesion molecule-1 (ICAM-1) were measured in 189 non-smokers and 76 smokers (aged 20-55 years) genotyped for the GSTM1 and T1 polymorphisms. Accounting for age and sex, smokers lacking GSTM1 had a higher WBC count, CRP and ICAM-1 levels as compared to the other groups; interaction term between smoking and genotype being significant (p=0.05). Conversely, non-smokers lacking GSTM1 had a higher levels of TNF-a; the test for interaction being significant (p=0.05). No significant interaction was found between smoking and GSTT1 genotypes, considering the 9 biological indices. However, significantly lower levels of IL-6 were noticed for non-smokers with GSTT1-0 null allele (p=0.05). Our study confirms previous results showing that GSTM1 polymorphism could modulate the interrelationships between smoking and biological markers of inflammation and endothelial function

The role of glutathione S-transferase GliG in gliotoxin biosynthesis in aspergillus fumigatus

Gliotoxin, a redox-active metabolite, is produced by the opportunistic fungal pathogen Aspergillus fumigatus, and its biosynthesis is directed by the gli gene cluster. Knowledge of the biosynthetic pathway to gliotoxin, which contains a disulfide bridge of unknown origin, is limited, although L-Phe and L-Ser are known biosynthetic precursors. Deletion of gliG from the gli cluster, herein functionally confirmed as a glutathione S-transferase, results in abrogation of gliotoxin biosynthesis and accumulation of 6-benzyl-6-hydroxy-1-methoxy-3-methylenepiperazine-2,5-dione. This putative shunt metabolite from the gliotoxin biosynthetic pathway contains an intriguing hydroxyl group at C-6, consistent with a gliotoxin biosynthetic pathway involving thiolation via addition of the glutathione thiol group to a reactive acyl imine intermediate. Complementation of gliG restored gliotoxin production and, unlike gliT, gliG was found not to be involved in fungal self-protection against gliotoxin