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Dietary folate deficiencies and drugs that interfere with folate metabolism, eg, methotrexate, an anti-carcinogenic agent that inhibits dihydrofolate reductase, and nitrous dioxide (N 2 O), an anesthetic gas that inhibits methionine synthase activity, lead to accumulations and cellular effluxes of homocysteine, causing increases in circulating homocysteine levels (Ueland and Refsum, 1989)