Genotype-independent in vivo oxidative stress following a methionine loading test: Maximal platelet activation in subjects with early-onset thrombosis

Background: methionine ingestion (100 mg/kg) identifies subjects in whom fasting total homocysteine (tHcy) may be normal but the post-methionine load (PML) tHcy is abnormally high. Methods: In 96 subjects [54 M/42 F, 40.4 ± 12.3 yrs old; 28 with the 68 bp844 ins of the Cystathionine-β-synthase gene (CBSins+); 20 homozygotes for the C677T mutation of the methylene-tetrahydrofolate reductase gene (MTHFR++); 13 with the combination of the two, and 35 without any of them], we have evaluated in vivo oxidative stress and platelet activation, as reflected by urinary excretions of 8-iso-PGF _2α and of 11-dehydro-TXB ₂ respectively, before and after a methionine load test (PML). A history of early-onset thrombosis (18 arterial, 32 venous, 2 both) was present in 52/96 of them. Results: Baseline; tHcy was highest in MTHFR++ carriers (p <0,05); 8-iso-PGF _2α and 11-dehydro-TXB ₂ levels were independent of sex, MTHFR++ and/or CBSins + (p > 0.05). PML; The ~ 3-fold increase (p <0.01 vs baseline) in tHcy reached a plateau within 6-8 hrs. Mean PML tHcy was maximal in MTHFR++ carriers (p = 0.000). 8-iso-PGF _2α and 11-dehydro-TXB ₂ increase reached a maximum within 4 hrs. 11-dehydro-TXB ₂ increase was highest (p = 0.023 vs baseline) in subjects with a history of thrombosis. Baseline 11-dehydro-TXB ₂ and a history of thrombosis independently predicted PML 11-dehydro-TXB ₂ (β = 0.287, p = 0.000 and β = 0.308, p = 0.026, respectively).The PML increase in 8-iso-PGF _2α or in 11-dehydro-TXB ₂ were comparable in the different genotypes (p > 0.05). Conclusion: regardless genotypes associated with moderate hyperhomocysteinemia, following a methionine loading test, in vivo oxidative stress and platelet activation occur, being the latter maximal in subjects with a history of early-onset thrombosis.