Metabolism of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine and their deuterated analogs by liver microsomes of rat and hamster.
Metabolism of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine and their deuterated analogs by liver microsomes of rat and hamster.
复制标题
N-亚硝基-2,6-二甲基吗啉及其氘化类似物的顺式和反式异构体在大鼠和仓鼠肝微粒体中的代谢。
DOI：
10.1093/carcin/5.8.1009
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发表时间：
1984
期刊：
影响因子：
4.7
通讯作者：
Scarpelli,DG
中科院分区：
文献类型：
--
作者：
Kokkinakis,D;Hollenberg,PF;Scarpelli,DG
雄性叙利亚金黄地鼠和Sprague道利大鼠肝微粒体将N-亚硝基-2，6-二甲基吗啉（NNDM）的异构体和反异构体代谢为N-亚硝基-（2-羟丙基）（2-氧代丙基）胺（HPOP）。顺式和反式异构体的总代谢率相似;但在仓鼠和大鼠中，NNDM的顺式异构体产生的HPOP占总产物的70%以上，而反式异构体产生的HPOP仅为次要产物（20-30%）。无法鉴别其他产物可归因于α-羟基化，这导致NNDM断裂和氚标记损失至水中。为了研究参与α-羟基化反应的可能性，检查了在3和5（α-d4）或2和6（β-d2）位完全氘代的NNDM的代谢，并与未氘代化合物（d 0）的代谢进行比较。虽然所有的顺式和反式衍生物的NNDM的代谢率是相似的（Vmax = 2.13 nmol/min/mg仓鼠微粒体蛋白），从测量的底物消失，HPOP的产量是不同的。顺式α-（d4）NNDM的HPOP产率最高（93.9%），其次为顺式0 NNDM（72.3%）、反式α-（d4）NNDM（60.1%）、反式0 NNDM（30.2%）、顺式β-（d2）NNDM（19.5%）和反式β-（d2）NNDM（8.5%）。这些结果表明α-羟基化是β-羟基化的替代方案。由于NNDM的各种氘衍生物对叙利亚金黄仓鼠的致癌效力与其产生HPOP的能力平行，因此β-羟基化与仓鼠的胰腺致癌作用密切相关。大鼠肝微粒体组分显示出与仓鼠肝微粒体相同的HPOP形成与总代谢产物产量的模式，同时具有顺式和反式异构体。然而，仓鼠的NNDM代谢和HPOP形成速率比大鼠肝微粒体快7倍。这种差异可能与顺式异构体未能诱导大鼠胰腺癌有关。
Liver microsomes from male Syrian golden hamsters and Sprague Dawley rats metabolize thecisandtransisomers of N-nitroso-2,6-dimethylmorpholine (NNDM) to N-nitroso-(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) as the major product detectable by h.p.l.c. The rates of total metabolism are similar for both the cis and trans isomers; but the cis isomer of NNDM yields >70% of the total product as HPOP while the trans isomer yields HPOP only as a minor product (20–30%) in both hamster and rat. The inability to identify other products could be attributed to α-hydroxylation which leads to fragmentation of NNDM and loss of tritium label to water. In order to investigate the possibility of the participation of an α-hydroxylation reaction, the metabolism of NNDM fully deuterated at either the 3 and 5 (α-d4) or the 2 and 6 (β-d2) positions was examined and compared to the metabolism of the undeuterated compound (d0). Although the rates of metabolism of all of the cis and trans derivatives of NNDM were similar (Vmax = 2.13 nmol/min/mg hamster microsomal protein) as determined from measurements of substrate disappearance, the yields of HPOP were different. Maximum HPOP yields were observed withcisα-(d4) NNDM (93.9% of the total), followed bycisd0NNDM (72.3%), trans α-(d4) NNDM (60.1%),transd0NNDM (30.2%),cisβ-(d2) NNDM (19.5%) and trans β-(d2) NNDM (8.5%). These results suggest that a-hydroxylation is an alternative to β-hydroxylation. Since the carcinogenic potency of the various deuterium derivatives of NNDM for the Syrian golden hamster parallels their ability to yield HPOP, β-hydroxylation is closely related to pancreatic carcinogenesis in the hamster. Rat liver microsomal fractions showed the same patterns of HPOP formation to total metabolite yields as hamster liver microsomes with both thecisandtransisomers. However, rates of NNDM metabolism and HPOP formation were 7 times faster with hamster than with rat liver microsomes. Such a difference may be related to the failure of the cis isomer to induce pancreatic cancer in rats.