GlutathioneS-transferase-mediated induction of GC → AT transitions by halomethanes in salmonella

Abstract

Halomethanes are among the most common mutagenic and carcinogenic disinfection by‐products present in the volatile/semivolatile fraction of chlorinated drinking water. Recent studies have demonstrated that the mutagenicity of dichloromethane (CH2Cl2) and bromodichloromethane (BrCHCl2) can be mediated by a theta‐class glutathione S‐transferase (GSTT1‐1). These studies used strain RSJ100 of Salmonella, which is a derivative of the base‐substitution strain TA1535 (hisG46, rfa, δuvrB), into which has been cloned the GSTT1‐1gene from rat. In the present report, we have ex tended these studies by demonstrating that the mutagenicity of two additional brominated trihalomethanes, bromoform (CHBr3) and chlorodibromomethane (ClCHBr2), are also mediated by GSTT1‐1 in RSJ100. Using a Tedlar bag vaporization technique, the mutagenic potencies (revertants/ppm) for these two compounds as well as the compounds tested previously rank as follows: CHBr3 ≈ ClCHBr2 > BrCHCl2 ≈ CH2Cl2. To explore the mutational mechanism, we determined the mutation spectra of all four halomethanes at the hisG46 allele by per forming colony probe hybridizations of ∼100 revertants induced by each compound. The majority (96–100%) of the mutations were GC → AT transitions, and 87–100% of these were at the second position of the CCC/GGG target. In contrast, only15% of mutants induced by CH2Cl2 were GC → AT transitions in the absence of the GSTT1‐1 gene in strain TA100 (a homologue of TA1535 containing the plasmid pKM101). The ability of GSTT1‐1 to mediate the mutagenicity of these di‐ and trihalomethanes and the induction of almost exclusively GC → AT transitions by these compounds suggest that these halomethanes are activated by similar pathways in RSJ100, possibly through similar reactive intermediates. The implications of these findings are discussed in relation to previous experimental work on the GST‐mediated bioactivation of dihalomethanes, which includes the possible formation of GSH intermediates and/or GSH‐DNAadducts. Environ. Mol. Mutagen. 30:440–447, 1997 Published 1997 Wiley‐Liss, Inc.

Genotoxic Effects in Swimmers Exposed to Disinfection By-products in Indoor Swimming Pools

“…Evaluation of polymorphisms in GSTT1 , a gene involved in the metabolism of brominated THMs, has indicated significantly stronger associations between THM exposure and bladder cancer among subjects with functioning GSTT1 (+/+ or +/− genotypes) than among subjects with deletions in both alleles (−/−) (Cantor et al 2010). This was consistent with early studies showing that GSTT1 activated the brominated THMs, but not chloroform, to mutagens in a transgenic strain of Salmonella (DeMarini et al 1997; Pegram et al 1997). GSTZ1 catalyzes the oxygenation of dichloroacetic acid to glyoxylic acid and plays a critical role in the tyrosine degradation pathway and in alpha-haloacid metabolism (Board and Anders 2005).…”

“…Chloroform is not mutagenic; however, the brominated THMs are, and they are activated to mutagens by glutathione S- transferase theta-1 (GSTT1) (DeMarini et al 1997; Pegram et al 1997). Bromodichloromethane has been shown to induce mutagenic activity in human urine (Leavens et al 2007).…”

Peer Reviewed: Disinfection Byproducts: The Next Generation

“…EPA researchers found a pathway for the metabolic activation of bromodichloromethane, through conjugation with glutathione (a tripeptide present in all animal cells) that results in bromodichloromethane-induced genotoxicity (45). Although this mutagenicity pathway is of relatively little importance for chloroform (45), it is important for bromoform and chlorodibromomethane (46), suggesting that the role of glutathione-mediated metabolic activation in the toxicity of brominated DBPs should be investigated further. Understanding the DBP metabolic pathways is important because in some cases a metabolite of the parent compound is the actual toxicant.…”

Exposure to Brominated Trihalomethanes in Water During Pregnancy and Micronuclei Frequency in Maternal and Cord Blood Lymphocytes

“…There is limited biologic support in the literature for an interaction with smoking. Smoking has been shown to increase expression of glutathione S -transferase (GST) (Thum et al 2006), which is a key metabolic pathway for the biotransformation and genotoxicity of BTHM (DeMarini et al 1997; Pegram et al 1997). …”

“…If the critical window of exposure was during the first trimester, then the cord blood lymphocytes collected at birth may not have been exposed. Another possible biologic explanation is that certain BTHM are metabolized by GST to reactive mutagens (DeMarini et al 1997; Pegram et al 1997), and it is likely that in utero metabolism of BTHM is immature, resulting in a lower exposure of the reactive toxic metabolites of THM to the fetus (Wild and Kleinjans 2003). …”