Shirota F N, Stevens-Johnk J M, DeMaster E G, Nagasawa H T
Medical Research Laboratories, VA Medical Center, Minneapolis, Minnesota, USA.
J Med Chem. 1997 Jun 6;40(12):1870-5. doi: 10.1021/jm9606296.
S-Methylisothiourea (4), when administered to rats followed by a subsequent dose of ethanol, gave rise to a 119-fold increase in ethanol-derived blood acetaldehyde (AcH) levels-a consequence of the inhibition of hepatic aldehyde dehydrogenase (A1DH)-when compared to control animals not receiving 4. The corresponding O-methylisourea was totally inactive under the same conditions, suggesting that differential metabolism may be a factor in this dramatic difference between the pharmacological effects of O-methylisourea and 4 in vivo. The S-n-butyl- and S-isobutylisothioureas (8 and 9, respectively) at doses equimolar to that of 4 were nearly twice as effective in raising ethanol-derived blood AcH, while S-allylisothiourea (10) was slightly less active. However, blood ethanol levels of all experimental groups were indistinguishable from controls. Pretreatment of the animals with 1-benzylimidazole, a known inhibitor of the hepatic mixed function oxidases, followed sequentially by either 8, 9, or 10 plus ethanol, reduced blood AcH levels by 66-88%, suggesting that the latter compounds were being oxidatively metabolized to a common product that led to the inhibition of AcH metabolism. In support of this, when 8 was incubated in vitro with rat liver microsomes coupled to catalase and yeast A1DH, the requirement for microsomal activation for the inhibition of A1DH activity was clearly indicated. We suggest that S-oxidation is involved and that the S-oxides produced in vivo inhibited A1DH directly, or spontaneously released cyanamide, an inhibitor of A1DH. Indeed, incubation of 8 with rat liver microsomes and NADPH gave rise to cyanamide as metabolite, identified as its dansylated derivative. Cyanamide formation was minimal in the absence of coenzyme. Extending the side chain was detrimental, since S-benzylisothiourea (11) and S-n-hexadecylisothiourea (12) were toxic, the latter producing extensive necrosis of the liver and kidneys when administered to rats.
给大鼠注射S-甲基异硫脲（4），随后给予乙醇，与未接受4的对照动物相比，乙醇衍生的血液乙醛（AcH）水平增加了119倍，这是肝醛脱氢酶（A1DH）受抑制的结果。在相同条件下，相应的O-甲基异脲完全无活性，这表明差异代谢可能是O-甲基异脲和4体内药理作用存在显著差异的一个因素。S-正丁基异硫脲和S-异丁基异硫脲（分别为8和9）在与4等摩尔剂量时，提高乙醇衍生血液AcH的效果几乎是其两倍，而S-烯丙基异硫脲（10）的活性略低。然而，所有实验组的血液乙醇水平与对照组无差异。用已知的肝混合功能氧化酶抑制剂1-苄基咪唑对动物进行预处理，然后依次给予8、9或10加乙醇，可使血液AcH水平降低66%-88%，这表明后几种化合物被氧化代谢为一种共同产物，从而导致AcH代谢受到抑制。支持这一观点的是，当8与大鼠肝微粒体、过氧化氢酶和酵母A1DH在体外孵育时，明显表明抑制A1DH活性需要微粒体激活。我们认为涉及S-氧化，体内产生的S-氧化物直接抑制A1DH，或自发释放氰胺，一种A1DH抑制剂。事实上，8与大鼠肝微粒体和NADPH孵育产生氰胺作为代谢产物，鉴定为其丹磺酰化衍生物。在没有辅酶的情况下，氰胺形成极少。延长侧链是有害的，因为S-苄基异硫脲（11）和S-正十六烷基异硫脲（12）有毒，后者给大鼠给药时会导致肝脏和肾脏广泛坏死。
