ABSTRACT
The susceptibility of an individual to oral cancer is mediated by genetic factors and carcinogen-exposure behaviors such as betel quid chewing, tobacco use, and alcohol consumption. This pilot study was aimed to identify the genetic alteration in 100 bp upstream and downstream flanking regions in addition to the exonic regions of 169 cancer-associated genes by using Next Generation sequencing with aim to elucidate the molecular pathogenesis of tobacco- and betel quid-associated oral cancer of Northeast India. To understand the role of chemical compounds present in tobacco and betel quid associated with the progression of oral cancer, single nucleotide polymorphisms (SNPs) and insertion and deletion (Indels) found in this study were analyzed for their association with chemical compounds found in tobacco and betel quid using Comparative Toxogenomic Database. Genes (AR, BRCA1, IL8, and TP53) with novel SNP were found to be associated with arecoline which is the major component of areca nut. Genes (BARD1, BRCA2, CCND2, IGF1R, MSH6, and RASSF1) with novel deletion and genes (APC, BRMS1, CDK2AP1, CDKN2B, GAS1, IGF1R, and RB1) with novel insertion were found to be associated with aflatoxin B1 which is produced by fermented areca nut. Genes (ADH6, APC, AR, BARD1, BRMS1, CDKN1A, E2F1, FGFR4, FLNC, HRAS, IGF1R, IL12B, IL8, NBL1, STAT5B, and TP53) with novel SNP were found to be associated with aflatoxin B1. Genes (ATM, BRCA1, CDKN1A, EGFR, IL8, and TP53) with novel SNP were found to be associated with tobacco specific nitrosamines.
Subject(s)
Areca/adverse effects , Genetic Predisposition to Disease/genetics , Mouth Neoplasms/genetics , Nicotiana/adverse effects , Polymorphism, Single Nucleotide , Adult , Aflatoxin B1/poisoning , Aged , Areca/chemistry , Arecoline/poisoning , Chromosome Mapping , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , INDEL Mutation , Male , Middle Aged , Mouth Neoplasms/etiology , Pilot ProjectsABSTRACT
The areca nut is the most widely consumed psychoactive substance in Taiwan, India, and Southeast Asia. It is considered to be an environmental risk factor for the development of oral submucous fibrosis and cancer. Arecoline, the major alkaloid of areca nut, has been known to cause cytotoxicity and genotoxicity in various systems. However, the active compound accounting for arecoline-induced damage in normal human oral cells is still uncharacterized. The present study was undertaken to identify the active metabolite of arecoline that might induce damage in human oral tissues and cause mutagenicity in Salmonella typhimurium tester strains TA 100 and TA 98. It is interesting to find that the major metabolite of arecoline, arecoline N-oxide, is moderately mutagenic to these Salmonella tester strains. This mutagenicity was potently inhibited by sulfhydryl compounds, namely, glutathione, N-acetylcysteine, and cysteine, whereas methionine is inactive in this inhibition. The mutagenicity of arecoline N-oxide was strongly inhibited by the N-oxide reducing agent titanium trichloride. The possible role of arecoline N-oxide in the induction of oral carcinogenesis by areca nut chewing is discussed.
Subject(s)
Areca/chemistry , Arecoline/analogs & derivatives , Carcinogens , Cyclic N-Oxides/toxicity , Mouth Neoplasms/chemically induced , Mutagens , Arecoline/poisoning , Arecoline/toxicity , Cyclic N-Oxides/poisoning , Humans , Mutagenicity Tests , Nuts/chemistry , Poisoning , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Sulfhydryl Compounds/pharmacology , Temperature , Titanium/pharmacologySubject(s)
Antidepressive Agents/pharmacology , Phenylalanine/analogs & derivatives , Animals , Antidepressive Agents/therapeutic use , Antidepressive Agents/toxicity , Arecoline/poisoning , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catecholamines/urine , Hypothermia/chemically induced , Mice , Nicotine/poisoning , Phenylalanine/pharmacology , Phenylalanine/therapeutic use , Phenylalanine/toxicity , Poisoning/drug therapy , RatsABSTRACT
In experiments on mice and rats it was shown that the studied calcium channel blockers--verapamil (finoptin, isoptin), nifedipine (corinfar), sensit (phendilin), cinnarizine (stugeron), diltiazem--are heterogeneous by their pharmacological properties. No relationships between the antiarrhythmic, anticonvulsant and cholinolytic effects of the compounds were revealed. It was supposed that the cholinolytic activity of nifedipine and diltiazem in arecoline salivation test reflects not their competitive relations with acetylcholine on the active surface of the receptor, but rather is realized at the level of the signal transmembrane transmission systems.
