Circadian variation in O-6-methylguanine-DNA methyltransferase activity in mouse liver
Circadian variation in O-6-methylguanine-DNA methyltransferase activity in mouse liver
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DOI：
10.1097/00001813-199608000-00012
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发表时间：
1996-08-01
影响因子：
2.3
通讯作者：
Levi, F
中科院分区：
文献类型：
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作者：
MartineauPivoteau, N;CussacBuchdahl, C;Levi, F
双功能氯乙基化细胞抑制剂会由于 O-6-烷基鸟嘌呤的形成而产生致命的 DNA 损伤。这些损伤可以通过 O-6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 进行修复，这种普遍存在的核和胞质酶通过将烷基接受到其活性位点的半胱氨酸残基来去除烷基，从而防止 DNA 链间交联的形成。在雄性 B6D2F1 小鼠中检查了昼夜节律组织在针对此类 DNA 损伤的细胞保护中的作用，同步进行 12 小时光照和 12 小时光照交替黑暗（LD12：12）。在八个不同的昼夜节律时间（相隔 3 小时）获得的小鼠肝脏中测定 MGMT 活性，MGMT 活性沿 24 小时时间尺度变化 B 倍，从光开始后 7 小时（HALO）时的 7 +/- 1 pmol/g 组织，到休息期间，在 19 HALO（第二个中后期活动时间段）时高达 32 +/- 9 pmol/g。 MGMT 活性的这种大幅昼夜节律可能是烷化剂敏感性节律的重要决定因素。最大的 DNA 修复活动发生在夜间，此时小鼠活跃、进食和饮水，因此暴露于化学损伤的风险较高。
Bifunctional chloroethylating cytostatic agents produce lethal DNA lesions, as a result of the formation of O-6-alkylguanines. These lesions can be repaired by O-6-methylguanine-DNA methyltransferase (MGMT), This ubiquitous nuclear and cytosolic enzyme removes the alkyl group by accepting it to the cysteine residue of its active site, thus preventing the formation of DNA interstrand cross-links, The role of the circadian organization in cellular protection against such DNA insults was examined in male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (LD12:12). MGMT activity was determined in liver of mice obtained at eight different circadian times, located 3 h apart, MGMT activity varied B-fold along the 24 h time-scale, from 7 +/- 1 pmol/g of tissue at 7 h after light onset (HALO), during the rest span, up to 32 +/- 9 pmol/g at 19 HALO (second mid to late activity span). This large amplitude circadian rhythm in MGMT activity may be an important determinant of the susceptibility rhythms to alkylating agents, The greatest DNA repair activity occured at night when mice were active, eat and drink, and thus are at a higher risk of being exposed to chemical insults.