Journal Article

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

Peri Noori and Sai-Mei Hou

in Carcinogenesis

Volume 22, issue 11, pages 1825-1830
Published in print November 2001 | ISSN: 0143-3334
Published online November 2001 | e-ISSN: 1460-2180 | DOI:
Mutational spectrum induced by acetaldehyde in the HPRT gene of human T lymphocytes resembles that in the p53 gene of esophageal cancers

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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.

Keywords: AA, acetaldehyde; HPRT, hypoxanthine-guanine phosphoribosyl transferase; BPDE, benzo[a]pyrene diolepoxide; XP, xeroderma pigmentosum.

Journal Article.  5957 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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