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Sex-related differences in methionine metabolism and plasma homocysteine concentrations^1,2,3

¹ From the General Clinical Research Center, Department of Medicine, Fletcher Allen Healthcare and College of Medicine, and the Department of Nutrition and Food Sciences, College of Agriculture and Life Sciences, University of Vermont, Burlington.

Background: Elevated fasting homocysteine concentrations are considered a risk factor for vascular disease. Homocysteine, which is produced by the transmethylation of methionine, can be either remethylated back to methionine or metabolized via transsulfuration to cystathionine. It has been speculated that the lower risk of vascular disease among premenopausal women may be related to lower homocysteine concentrations in women than in men.

Objective: This study was designed to determine whether sex-related differences exist in methionine cycle kinetics, which may account for the reportedly lower fasting homocysteine concentrations in premenopausal women.

Design: Eleven healthy young men and 11 premenopausal women without cardiac risk factors were studied by using stable-isotope-labeled L-[methyl-²H₃,1-¹³C]methionine and L-[methyl- ²H₃]leucine. After 3 h of tracer infusion, 100 mg unlabeled L-methionine/kg body wt was ingested. Blood and breath samples were obtained at timed intervals. Fat-free mass was estimated by dual-energy X-ray absorptiometry and muscle mass by urinary creatinine excretion.

Results: No significant sex-related differences were found in fasting homocysteine concentrations, responses to the oral methionine load, or rates of methionine flux based on carboxyl or methyl labels. However, women had significantly higher remethylation rates than did men (P < 0.005) and a tendency toward higher transmethylation (P < 0.10). Whereas adjustment of remethylation rates for fat-free mass tended to attenuate the sex-related effect (P = 0.08), adjustment for muscle mass did not (P < 0.04). In contrast, significant sex-related differences in leucine flux (P < 0.02) were eliminated after adjustment for either fat-free mass or muscle mass.

Conclusion: Reported differences between men and women in homocysteine concentrations may be partially explained by differences in rates of homocysteine remethylation.

Key Words: Homocysteine • sex • amino acids • kinetics • sulfur amino acids • methionine • cysteine • premenopausal women • remethylation

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