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Homocysteine clearance and methylation flux rates in health and end-stage renal disease: association with S-adenosylhomocysteine

¹Department of Internal Medicine, ²Institute for Cardiovascular Research, ⁴Department of Nephrology, and ⁵Department of Clinical Chemistry, Vrije Universiteit Medical Center, 1081 HV Amsterdam; and ³Department of Internal Medicine, Amphia Hospital, 4800 RL Breda, The Netherlands

Submitted 28 October 2003 ; accepted in final form 25 March 2004

Hyperhomocysteinemia is a risk factor for cardiovascular disease and occurs frequently in end-stage renal disease (ESRD), but its pathogenesis is poorly understood. We aimed to evaluate one-carbon flux rates of methionine and homocysteine (Hcy) in ESRD patients and healthy controls. Transmethylation (TM), remethylation (RM), and transsulfuration (TS), as well as Hcy clearance by TS (i.e., TS/plasma total Hcy concentration) and by RM (i.e., RM/plasma total Hcy concentration) were evaluated in relation to body composition, vitamins, and S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) levels. After a fixed protein diet for 3 days, primed-continuous infusion of [²H₃-methyl-1-¹³C]methionine was performed in the postabsorptive state in 12 hemodialysis patients and 16 healthy volunteers. Hcy clearance by TS (–80%, P < 0.001) and by RM (–77%, P < 0.001) in ESRD patients was decreased compared with healthy controls. The absolute flux rates of TM (–27%, P < 0.01) and RM (–28%, P = 0.02) were lower in the ESRD patients. After adjustment for age, TS was not significantly reduced. Whole blood AdoHcy was significantly elevated in ESRD and was a significant determinant of TM (standardized = –1.24, P = 0.01) and RM (standardized = –1.43, P = 0.03). In conclusion, patients with ESRD have impaired Hcy clearance by TS and RM. Elevated whole blood AdoHcy levels are associated with impaired RM and TM flux rates in these patients, and AdoHcy may be a key regulatory compound in one-carbon flux.

stable isotopes; S-adenosylmethionine; transsulfuration; remethylation; transmethylation

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