Элькар, витамин В6 и гомоцистеинурия

[rodrn]

Уважаемая audovichenko,

Полностью поддерживая Вашу оценку данного клинического случая, не соглашусь со следующей фразой.

Сообщение от audovichenko

Ни элькар, ни витамин В6 ничего не лечат (кроме авитаминоза по В6 - достаточно редкого явления)...

Например, гомоцистеинурия. Привести ссылки?

Еще раз подчеркиваю, что речь не идет о данном пациенте.

[rodrn]

Все никак не могу освоится с особенностями виртуальной медицинской помощи.
Хотелось бы узнать мнение коллег с кардиологической ветки форума.
http://forums.rusmedserv.com/showthread.php?t=104236

[Dr.Vad]

Кроме сугубо пищевого отсутствия витамина В6, под которым мы привыкли подразумевать авитаминоз, существует группа других состояний и болезней, при которых вследствие дефекта или лек. взаимодействия, возникает относительный дефицит/гиповитаминоз витамина В6, когда для коррекции требуются б0льшие дозы, чем обычные профилактические. Такие состояния/болезни называются пиридоксин-зависимыми, но эффективность назначения пиридиксина при них может колебаться от 100% до 5%. Для таких состояний болезней очень важна точная диагностика, так как назначение витамина В6 вслепую при "похожей симптоматике" может нанести вред организму, напр. вызвав пиридоксиновую нейропатию. Об этом и др. подробнее напр. в обзоре:

J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):317-26.
B6-responsive disorders: a model of vitamin dependency.
Clayton PT.
Biochemistry, Endocrinology and Metabolism, Institute of Child Health, 30 Guilford St, London, WC1N 1 EH, UK.

Pyridoxal phosphate is the cofactor for over 100 enzyme-catalysed reactions in the body, including many involved in the synthesis or catabolism of neurotransmitters. Inadequate levels of pyridoxal phosphate in the brain cause neurological dysfunction, particularly epilepsy. There are several different mechanisms that lead to an increased requirement for pyridoxine and/or pyridoxal phosphate. These include: (i) inborn errors affecting the pathways of B(6) vitamer metabolism; (ii) inborn errors that lead to accumulation of small molecules that react with pyridoxal phosphate and inactivate it; (iii) drugs that react with pyridoxal phosphate; (iv) coeliac disease, which is thought to lead to malabsorption of B(6) vitamers; (v) renal dialysis, which leads to increased losses of B(6) vitamers from the circulation; (vi) drugs that affect the metabolism of B(6) vitamers; and (vii) inborn errors affecting specific pyridoxal phosphate-dependent enzymes. The last show a very variable degree of pyridoxine responsiveness, from 90% in X-linked sideroblastic anaemia (delta-aminolevulinate synthase deficiency) through 50% in homocystinuria (cystathionine beta-synthase deficiency) to 5% in ornithinaemia with gyrate atrophy (ornithine delta-aminotransferase deficiency). The possible role of pyridoxal phosphate as a chaperone during folding of nascent enzymes is discussed. High-dose pyridoxine or pyridoxal phosphate may have deleterious side-effects (particularly peripheral neuropathy with pyridoxine) and this must be considered in treatment regimes. None the less, in some patients, particularly infants with intractable epilepsy, treatment with pyridoxine or pyridoxal phosphate can be life-saving, and in other infants with inborn errors of metabolism B(6) treatment can be extremely beneficial.

[rodrn]

Отличная ссылка. Спасибо!
Кстати, что касается inborn errors affecting specific pyridoxal phosphate-dependent enzymes, к которым относится гомоцистеинурия, то при них-то как раз дефицита B6 нет, а для терапии он все равно используется. Парадокс? Или кто-то может объяснить это с точки зрения молекулярной биологии/биохимии?

[Dr.Vad]

Тоже недавняя работа:

Hum Mutat. 2006 May;27(5):474-82.
Contrasting behaviors of mutant cystathionine beta-synthase enzymes associated with pyridoxine response.
Chen X, Wang L, Fazlieva R, Kruger WD.
Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Cystathionine beta-synthase (CBS) deficiency is a recessive genetic disorder characterized by extremely elevated levels in plasma homocysteine. Patients homozygous for the I278T or R266K mutations respond clinically to pharmacologic doses of pyridoxine, the precursor of a cofactor for the enzyme, 5'-pyridoxal phosphate (PLP). Here we test the hypothesis that these mutations are pyridoxine responsive because they lower the affinity of the enzyme for PLP. We show that recombinant R266K has 30 to 100% of the specific activity of the wild-type enzyme, while I278T only has only 1 to 5% activity. Kinetic studies show that the decreased activity in both enzymes is due to reduced turnover rate and not substrate binding. Neither I278T nor R266K appear to greatly affect multimer status of the enzyme. The R266K enzyme has reduced affinity for PLP compared to the wild-type enzyme, providing a mechanism for the pyridoxine response observed in patients. Surprisingly, the I278T enzyme does not have altered affinity for PLP. To confirm that this was not an in vitro artifact, we examined pyridoxine response in mice that stably express human I278T as their sole source of CBS activity. These mice have extremely elevated plasma homocysteine levels and do not respond significantly to large doses of pyridoxine. Our findings suggest that there may be multiple mechanisms involved in response to pyridoxine.

[rodrn]

Браво! Моя коллега по лаборатории как раз работала с этими мышами.