Nagele Peter, Zeugswetter Barbara, Eberle Corinna, Hüpfl Michael, Mittlböck Martina, Födinger Manuela
Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA.
Pharmacogenet Genomics. 2009 May;19(5):325-9. doi: 10.1097/FPC.0b013e328328d54c.
Oxidation of vitamin B12 by nitrous oxide leads to the inactivation of methionine synthase resulting in elevated plasma total homocysteine concentrations. Methionine synthase reductase is the only human enzyme that is able to reverse the oxidation of vitamin B12, which also occurs naturally by reactive oxygen species. A common polymorphism in methionine synthase reductase, MTRR 66A>G, is associated with reduced enzyme activity. Thus, we hypothesized that patients with this gene variant develop higher plasma total homocysteine concentrations after nitrous oxide anesthesia than wild-type patients.
In this follow-up investigation of a previous gene association study, we prospectively included 140 healthy individuals undergoing elective surgery under general anesthesia that included 66% nitrous oxide. Peak postoperative plasma total homocysteine was the main outcome variable and was measured within 2 h after the end of anesthesia. The MTRR 66A>G genotype was determined after completion of the study. The association between genotype and peak postoperative total homocysteine was modeled with a general linear model.
No association between MTRR 66A>G and immediate postoperative plasma total homocysteine after nitrous oxide anesthesia was detected. All three groups, stratified by genotype (MTRR 66AA, AG, GG), shared similar baseline characteristics and increases in plasma total homocysteine. The average increase in plasma homocysteine was 2.4 mumol/l (+28%) in all three groups indicating the expected inactivation of methionine synthase by nitrous oxide through oxidation of vitamin B12, but no genetic effect.
In conclusion, this study showed that the MTRR 66A>G gene variant is not associated with peak elevated postoperative plasma total homocysteine after nitrous oxide anesthesia. Whether the gene influences the rate of recovery of methionine synthase remains to be determined.
一氧化二氮可使维生素B12氧化，导致甲硫氨酸合成酶失活，从而使血浆总同型半胱氨酸浓度升高。甲硫氨酸合成酶还原酶是唯一能够逆转维生素B12氧化的人类酶，而维生素B12的氧化也可由活性氧自然引发。甲硫氨酸合成酶还原酶存在一种常见的多态性，即MTRR 66A>G，它与酶活性降低有关。因此，我们推测具有这种基因变异的患者在一氧化二氮麻醉后血浆总同型半胱氨酸浓度会高于野生型患者。
在这项对先前基因关联研究的随访调查中，我们前瞻性纳入了140例接受全身麻醉下择期手术的健康个体，麻醉中一氧化二氮浓度为66%。术后血浆总同型半胱氨酸峰值是主要观察变量，在麻醉结束后2小时内进行测量。研究结束后确定MTRR 66A>G基因型。采用一般线性模型对基因型与术后总同型半胱氨酸峰值之间的关联进行建模。
未检测到MTRR 66A>G与一氧化二氮麻醉后即刻术后血浆总同型半胱氨酸之间存在关联。按基因型（MTRR 66AA、AG、GG）分层的所有三组患者具有相似的基线特征和血浆总同型半胱氨酸升高情况。所有三组血浆同型半胱氨酸的平均升高幅度为2.4μmol/L（升高28%），表明一氧化二氮通过维生素B12氧化使甲硫氨酸合成酶失活，但不存在基因效应。
总之，本研究表明MTRR 66A>G基因变异与一氧化二氮麻醉后术后血浆总同型半胱氨酸峰值升高无关。该基因是否影响甲硫氨酸合成酶的恢复速率仍有待确定。
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