Repair and removal of azoxymethane-induced O⁶-methylguanine in rat colon by O⁶-methylguanine DNA methyltransferase and apoptosis

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• 作者：Laura S. Nyskohus ; Am ; a J. Watson ; Geoffrey P. Margison ; Richard K. Le Leu ; Susan W. Kim ; Trevor J. Lockett ; Richard J. Head ; Graeme P. Young ; Ying Hu
• 关键词：AOM ; azoxymethane ; O6-meG ; O6-methylguanine ; MGMT ; O6-methylguanine DNA methyltransferase ; DMH ; 1 ; 2-dimethylhydrazine ; CRC ; colorectal cancer ; DSB ; double-strand break
• 刊名：Mutation Research/Genetic Toxicology and Environmental Mutagenesis
• 出版年：12 December, 2013
• 年：2013
• 卷：758
• 期：1-2
• 页码：80-86
• 全文大小：1948 K

文摘

Azoxymethane (AOM) is an alkylating agent that generates mutagenic and carcinogenic O⁶-methylguanine (O⁶meG) adducts in DNA. O⁶meG has been detected in human colonic DNA; hence, understanding the innate cellular events occurring in response to the formation of O⁶meG is important in developing preventive strategies for colorectal cancer. We explored the time-course, dose-response, and kinetics of O⁶meG formation and its removal by the DNA repair protein, O⁶-methylguanine DNA methyltransferase (MGMT), and apoptosis. In rats given AOM (10 mg/kg), the formation of O⁶meG occurs within 2 h of exposure, accompanied by rapid depletion of MGMT activity and followed by the induction of an acute apoptotic response that peaks at 6-8 h. MGMT repair and apoptosis are dependent on AOM dose and O⁶meG load. Apoptosis is initiated only when a high O⁶meG load is present and MGMT activity is fully depleted. AOM, 10 mg/kg, overwhelms MGMT repair for about 96 h and renewed MGMT activity is only observed once O⁶meG is no longer detectable. A threshold for apoptosis is observed at 6 h after 6 mg/kg AOM, when a high O⁶meG persists and MGMT activity is very low. These data suggest that apoptosis is probably triggered by O⁶meG, but only once the capacity of MGMT to repair O⁶meG is exhausted. In the colonic epithelium, apoptosis may be complementary to MGMT, in terms of minimising potentially mutagenic events and maintaining a healthy genome.