Mutational spectrum induced by acetaldehyde in the HPRT gene of human T lymphocytes resembles that in the p53 gene of esophageal cancers

• Published in: Carcinogenesis (New York) Vol. 22; no. 11; pp. 1825 - 1830
• Main Authors: Noori, Peri, Hou, Sai-Mei
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-11-2001; Oxford Publishing Limited (England)
• Subjects: 6-thioguanine; acetaldehyde; Acetaldehyde - pharmacology; benzo[a]pyrene diolepoxide; Biological and medical sciences; BPDE; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA Mutational Analysis; DNA Primers - chemistry; DNA, Complementary - genetics; Esophageal Neoplasms - enzymology; Esophageal Neoplasms - etiology; Esophageal Neoplasms - genetics; Exons; Fundamental and applied biological sciences. Psychology; HPRT; HPRT gene; Humans; Hypoxanthine Phosphoribosyltransferase - genetics; hypoxanthine-guanine phosphoribosyl transferase; Medicin och hälsovetenskap; Molecular and cellular biology; p53 gene; Point Mutation - drug effects; Polymerase Chain Reaction; T-Lymphocytes - enzymology; Tumor Suppressor Protein p53 - genetics; xeroderma pigmentosum; Cell culture; Metabolite; Pathogenesis; Toxicity; Glycosyltransferases; Esophageal disease; Alcohol; Homology; Hypoxanthine phosphoribosyltransferase; Mutagen; Carcinogenesis; Acetaldehyde; TP53 Gene; Reporter gene; Tumor suppressor gene; Human; Enzyme; Transferases; Malignant tumor; In vitro; Esophagus; Carcinogen; Digestive diseases; Nucleotide transition; Mutation; Pentosyltransferases; Lymphocyte
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/22.11.1825

As the primary metabolite of alcohol, acetaldehyde (AA) may be responsible for many pathological effects related to consumption of alcohol, such as esophageal cancer. The spectrum of p53 mutations in esophageal tumors is indicative of the involvement of exogenous agents, such as tobacco smoke. There is, however, no experimental proof for the involvement of alcohol as data on mutational spectrum induced by AA in human genes is completely lacking. The aim of this study is to investigate whether AA leaves mutational fingerprint in the HPRT reporter gene in human peripheral T cells. Pre-existing in vivo HPRT mutants were removed from PHA-stimulated T lymphocytes before in vitro treatment with 2.4 mM AA for 24 h. Following cell growth to allow mutation expression, independent 6-thioguanine-resistant mutants were selected from large numbers of subcultures showing a 3-fold induction of mutant frequency on average. A total of 73 induced and 36 spontaneous mutants were found to carry a missense, nonsense, frameshift or splice mutation. Base substitutions were identified in the coding or splicing sequences of 55 induced and 26 control mutants. The induced base changes were mainly G > A transition (40%, G on non-transcribed strand) followed by A > T transversions (14.5%, A on non-transcribed strand). The control mutants had significantly (P = 0.04) less G > A transition (15.4%) and completely lacked A > T transversions. We also identified 5′-AGG-3′ or 5′-AAG-3′ as potential target sequences for AA-induced G > A transitions. This specific mutational spectrum induced by AA is consistent with the known formation and persistency of N2-ethyl-2′-guanosine adduct and with the predominance of G > A transitions and mutations at A:T base pairs in the p53 gene of esophageal tumors. We conclude that AA may be involved in the pathogenesis of esophageal cancer.