You are here:
MUTAGENICITY AND MUTATION SPECTRA OF AIR AND WATER: ROLE OF GSST1-1 AND AKR GENOTYPES
Citation:
DEMARINI, D. M. MUTAGENICITY AND MUTATION SPECTRA OF AIR AND WATER: ROLE OF GSST1-1 AND AKR GENOTYPES. Presented at Health Canada, Ontario, QC, CANADA, February 21, 2007.
Description:
Recent molecular epidemiology research confirms that an increased risk for bladder cancer is associated with dermal/inhalation exposure to chlorinated water (from bathing/showering and/or swimming), rather than to drinking the water, and that risk is enhanced in people carrying a wild type copy of the GSTT1-1 gene (i.e., glutathione-S¬transferase isoform T1-1). Dermal adsorption permits disinfection by-products to enter directly into the blood stream, bypass the liver, and be transported without significant metabolism to the colon and bladder. The relative proportion of GSTT1-1 activity, which activates brominated trihalomethanes, to the activities of P450 isozymes, is greater in the colon than in other potential target tissues such as the liver. Thus, the disinfection by¬products obtained through dermal exposure may be more likely to be activated to mutagens by GSTT1-1 in the colon and bladder, rather than inactivated by P450 isozymes in the liver, explaining the increased cancer risk in these organs. Unfortunately, no molecular epidemiology studies water have been performed to determine if mutation patterns in human tumors support this thesis, and further studies need to be conducted in both rodents and humans to clarify whether dermal and inhalation exposure to disinfection by-products can increase the risk for colorectal and bladder cancer. The particulate fraction of all urban air samples examined to date induce mutations in Salmonella, and fractionation studies indicate that polycyclic aromatic hydrocarbons (PAHs) are an important component of this mutagenic material. GC to TA mutations are the primary base substitutions induced by the particulate fraction of urban air, as well as by the primary mutagen in the volatile fraction of air, i.e., peroxyacetyl nitrate (PAN). Our studies of the mutations in the KRAS and P53 genes of lung tumors from women whose lung cancer is associated with exposure to PAH-rich smoky coal emissions show that the mutation spectrum in these genes reflects the PAH exposure, confirming that the mutations in tumors do reflect environmental mutagen exposures. Genotyping studies in the smoky coal-exposed population showed that individuals who are wild-type for the first gene in the aldo-keto reductase (AKR) pathway for oxidative metabolism of PAHs have a 13-fold increased risk for lung cancer. This suggests that the oxidative pathway of PAH metabolism, which induces a mixture of stable and unstable DNA adducts, may play an important role for lung cancer risk, along with the CYP P450 pathway, which also induces stable and unstable DNA adducts.