Barrows L R, Shank R C, Magee P N
Carcinogenesis. 1983 Aug;4(8):953-7. doi: 10.1093/carcin/4.8.953.
The treatment of rats with hepatotoxic doses of hydrazine (NH2-NH2) induces the rapid formation of 7-methylguanine and O6-methylguanine in liver DNA. The methyl moiety in these reactions might be derived from the cellular S-adenosylmethionine pool because radioactivity administered to these rats as methionine rapidly appears in the DNA as methylated guanine. An increased incorporation of radioactivity into 5-methylcytosine was previously reported followed by subsequent suppression. This increased radiolabeling of 5-methylcytosine coincided with time of maximal DNA guanine methylation. To determine the nature of S-adenosylmethionine metabolism during the period of DNA methylation induced by hydrazine treatment, and to determine if the increased radiolabeling of 5-methylcytosine at this time reflected an actual increase in 5-methylcytosine synthesis, liver DNA synthesis and S-adenosylmethionine levels and turnover were assayed. Liver S-adenosylmethionine concentrations varied slightly between control rats and hydrazinetreated rats during the first five hours after hydrazine administration, and no difference was detectable in the incorporation of administered [3H]methionine into S-adenosylmethionine. Because S-adenosylmethionine specific radioactivity in hydrazine-treated rats was not different from control rats, the previously observed increased radiolabeling of 5-methylcytosine appeared to represent an actual increase in synthesis. This conclusion was supported by finding that incorporation of radioactive thymidine into DNA was also accelerated immediately following hydrazine administration, again followed by a decrease. 5-Methylcytosine sythesis, therefore, appears to follow DNA synthesis during hydrazine toxicity, and formation of 7-methylguanine and O6-methylguanine in liver DNA of hydrazine-treated rats occurs during a short period of increased DNA sythesis and 5-methylcytosine formation very early in hydrazine toxicity.
用肝毒性剂量的肼（NH₂-NH₂）处理大鼠会导致肝脏DNA中迅速形成7-甲基鸟嘌呤和O⁶-甲基鸟嘌呤。这些反应中的甲基部分可能来源于细胞的S-腺苷甲硫氨酸池，因为作为甲硫氨酸给予这些大鼠的放射性物质会迅速以甲基化鸟嘌呤的形式出现在DNA中。先前报道了放射性物质掺入5-甲基胞嘧啶增加，随后又受到抑制。这种5-甲基胞嘧啶放射性标记的增加与DNA鸟嘌呤甲基化的最大值时间一致。为了确定肼处理诱导的DNA甲基化期间S-腺苷甲硫氨酸代谢的性质，并确定此时5-甲基胞嘧啶放射性标记的增加是否反映了5-甲基胞嘧啶合成的实际增加，对肝脏DNA合成、S-腺苷甲硫氨酸水平和周转率进行了测定。在给予肼后的前五个小时内，对照大鼠和经肼处理的大鼠肝脏中的S-腺苷甲硫氨酸浓度略有不同，并且在给予的[³H]甲硫氨酸掺入S-腺苷甲硫氨酸方面未检测到差异。由于经肼处理的大鼠中S-腺苷甲硫氨酸的比放射性与对照大鼠没有差异，因此先前观察到的5-甲基胞嘧啶放射性标记增加似乎代表了合成的实际增加。这一结论得到了以下发现的支持：在给予肼后，放射性胸苷掺入DNA也立即加速，随后再次下降。因此，在肼毒性期间，5-甲基胞嘧啶的合成似乎跟随DNA合成，并且在肼毒性早期DNA合成和5-甲基胞嘧啶形成增加的短时间内，经肼处理的大鼠肝脏DNA中会形成7-甲基鸟嘌呤和O⁶-甲基鸟嘌呤。
