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Pharmacogenetics of Nitrous Oxide

IT has long been known that nitrous oxide in clinically relevant doses and durations shuts down single carbon pathways by virtue of oxidation of the cobalamin cofactor of methionine synthase, the sole occupant at the crossroads of the methylation, transsulfuration, and folate cycles. Surprisingly, the clinical consequences of nitrous oxide–mediated, folate–cobalamin cycle inactivation have not restrained its use in the more than 150 yr that have elapsed since its introduction for surgical anesthesia. In part, this may be explained by preoperative cellular stores of S-adenosyl methionine that are adequate for most patients to ride out the days needed for enzyme resynthesis. In the current issue of ANESTHESIOLOGY, Nagele et al. suggest a corollary explanation. In their contribution, the authors show that although all patients experience modest elevations in homocysteine (i.e., S-adenosyl methionine’s amino acid substrate) after exposure to nitrous oxide, patients who are homozygous for polymorphisms in the gene encoding 5,10 methylene tetrahydrofolate reductase (MTHFR), the enzyme antecedent to methionine synthase in the folate cycle, may develop levels well above those associated with adverse pathophysiologic consequences. If confirmed and extended, these observations suggest that all patients are not equally at risk for homocysteine-associated nitrous oxide toxicity, that deleterious events after nitrous oxide exposure may be enriched in a subset of patients at greatest genetic predisposition, and that risk stratification by genotype may be a useful adjunct in judging who should inhale nitrous oxide, at what concentration, and for how long. Superimposition of an acquired lesion in methionine synthase on inborn lesions in 5,10 methylene tetrahydrofolate reductase leads to conjoined biochemical alterations, i.e., accumulation of the reaction substrate homocysteine, and deficiency of the reaction product S-adenosyl methionine. S-Adenosyl methionine is the direct methyl donor in more than 100 metabolic steps, including methylation of DNA, RNA, proteins, phospholipids, myelin, polysaccharides, choline, and neurotransmitters. Accordingly, hypomethylation impairs gene expression, cell growth, differentiation, and function that may underlie multiple conditions associated with prolonged or ill-timed exposure to nitrous oxide, including bone marrow depression, subacute combined degeneration of the spinal cord in adults after use and abuse, hazards of unscavenged occupational exposure, and neuronal toxicity in childhood. The role, if any, of hypomethylation secondary to genetic predispositions in these nitrous oxide syndromes is provocative, although incompletely understood at present. Homocysteine may accumulate as an innocent bystander, or as a nonspecific marker of enzyme inactivation, rather than as a primary participant in the pathologic cascade of methyl deficiency. In more common disorders of central interest to anesthesiologists, however, hyperhomocysteinemia rather than hypomethylation may be the dominant lesion. Moderate hyperhomocysteinemia (i.e., 12–30 M) most frequently arises from vitamin deficiency, renal insufficiency, and, as here, MTHFR mutations. Intermediate homocysteine levels between 30 and 100 M are often due to profound vitamin deficiency, kidney failure, and heterozygosity for cystathionine -synthase (CBS) polymorphisms, whereas severe elevations ( 100 M) are seen in rare patients with homozygous CBS mutations. Moderate to intermediate elevation of homocysteine injures the vascular endothelium, promotes coagulation, and impairs smooth muscle relaxation via inhibition of nitric oxide bioavailability, inactivation of factor Va, reduced antithrombin II and tissue plasminogen activator binding, increased resistance to fibrinolysis, vascular smooth muscle and foam cell proliferation, enhanced platelet activation and aggregation, increased expression of proinflammatory cytokines, and formation of reactive oxygen species, among numerous other established and proposed mechanisms. Whereas the association of hyperhomocysteinemia and venous thromboembolism is controversial on the basis of currently available clinical data, chronically elevated plasma homocystinemia is recognized as an independent risk factor for atherosclerosis and related arterial occlusive conditions (e.g., restenosis), particularly in patients with coexisting cardiovascular disease, acquired folate or cobalamin deficiencies, and MTHFR mutations. Hyperhomocysteinemia is also an independent risk factor for neurodegenerative diseases and dementia. In neurons, homocysteine competes for glutamate and aspartate receptors, and exacerbates oxidative stress, forThis article is featured in “This Month in Anesthesiology.” Please see this issue of ANESTHESIOLOGY, page 9A.