The role of chloride in tobacco-smoke-induced cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Tobacco smoke contains a large number of carcinogenic components, all participating to different degrees and with different potencies to initiate the development of cancer. Polycyclic aromatic hydrocarbons (PAHs) are a class of chemical carcinogens that occur as byproducts of organic combustion. Several members of this class are potent carcinogens and considerable amounts are found in tobacco smoke. Benzo[a]pyrene (BaP) is a well-studied tobacco component which causes tumors in animals and may cause lung tumors in humans. Over the past two decades studies have revealed how BaP and other PAHs cause DNA damage.
 
 
 
 
 
 In the process of eliminating these foreign chemicals from the body, cellular metabolism results in the formation of an intermediate compound, the BaP diol epoxide (BPDE), that can bind to DNA (i.e., form DNA adducts). These DNA addicts can cause mutations in genes whose products control cell growth (e.g., proto-oncogenes and tumor suppressor genes). To date, this metabolic activation and DNA binding process is incompletely understood. Recent evidence from our laboratory that suggests the existence of a previously unrecognized cellular pathway in the formation of DNA adducts. This pathway is catalyzed by one of the ions that form common table salt (sodium chloride). The chloride ion is present at high levels in lung cells, and test tube studies have shown that it alters the structure of cancer-causing adducts to form certain types of DNA adducts that may be more mutagenic than those formed without chloride present. Thus, chloride could play a role in mutagenesis and carcinogenesis. An additional indirect influence of chloride on tumor initiation in lung cells can be exerted by two different ways.
 
 
 
 
 
 First, changes in intracellular chloride concentrations can lead to differences in mutations at sensitive sites in DNA (such as within important genes). Second, chloride can interfere with DNA repair enzymes and thus increase the probability that these adducts will induce a mutation. To test this hypothesis, we must determine if chloride, which plays a role in numerous normal cell functions, could indirectly influence the mutagenicity of PAHs in vivo. For this purpose, cultured lung epithelial cells seem to be an appropriate model, since they (1) represent possible target cells in humans, (2) possess metabolic activation enzymes, (3) are able to proliferate in vivo, and (4) are involved in chloride transport in vivo. These cells will be exposed to drugs which cause either an increase or decrease in intracellular chloride concentration. Then these cells will be treated with BPDE and tested at different time points. The aim is to elucidate the possible synergistic effects between DNA adduct formation by BPDE and chemicals stimulating or inhibiting chloride channels (particularly tobacco smoke components) and to find a significant biological cancer risk marker for tobacco-induced tumors in humans.