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

Abstract

Backgroundmethionine ingestion (100mg/kg) identifies subjects in whom fasting total homocysteine (tHcy) may be normal but the post-methionine load (PML) tHcy is abnormally high. MethodsIn 96 subjects [54 M/42 F, 40.4±12.3yrs old; 28 with the 68bp844 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-PGF2α and of 11-dehydro-TXB2 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. ResultsBaseline; tHcy was highest in MTHFR++ carriers (p<0,05); 8-iso-PGF2α and 11-dehydro-TXB2 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 6–8hrs. Mean PML tHcy was maximal in MTHFR++ carriers (p=0.000). 8-iso-PGF2α and 11-dehydro-TXB2 increase reached a maximum within 4hrs. 11-dehydro-TXB2 increase was highest (p=0.023 vs baseline) in subjects with a history of thrombosis. Baseline 11-dehydro-TXB2 and a history of thrombosis independently predicted PML 11-dehydro-TXB2 (β=0.287, p=0.000 and β=0.308, p=0.026, respectively).The PML increase in 8-iso-PGF2α or in 11-dehydro-TXB2 were comparable in the different genotypes (p>0.05). Conclusionregardless 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.