Ravindranath V, Boyd M R
Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Frederick, MD 21702-1013.
Biochem Pharmacol. 1991 May 1;41(9):1311-8. doi: 10.1016/0006-2952(91)90102-b.
Treatment of male Sprague-Dawley rats with buthionine sulfoximine (BSO), prior to administration of carbon-14(14C)-labelled 2-methylfuran (2MF) caused a marked decrease in the covalent binding of 14C-labelled 2MF metabolites to both DNA and protein, although there was no apparent change in the distribution of the labelled parent 2MF. BSO pretreatment also protected against hepatotoxicity of 2MF, as indicated by lower serum glutamic pyruvic transaminase (GPT) levels. Pretreatment with BSO offered protection only if administered 1.5 hr before 2MF dosage. Administration of 2MF, 4 and 6 hr after BSO resulted in manifestation of the hepatotoxicity of 2MF. Prior treatment with diethylmaleate (DEM), increased covalent binding of [14C]2MF to liver proteins and also elevated serum GPT levels. Thus, depletion of tissue glutathione (GSH) by two different chemicals acting by different mechanisms produced opposite effects on the covalent binding and toxicity of 2MF. Pretreatment with L-2-oxothiazolidine-4-carboxylate (OTZ), a promoter of GSH biosynthesis, increased the hepatic covalent binding of [14C]2MF and potentiated hepatotoxicity. However, administration of OTZ and BSO prior to an i.p. dose of 100 mg/kg of 2MF, decreased the hepatic covalent binding of [14C]2MF and decreased the hepatoxicity. The marked instability of the GSH conjugate of the reactive metabolite of 2MF may account for the potentiation of hepatotoxicity of 2MF by OTZ. A single s.c. dose of BSO, caused a transient increase in plasma cystine levels concurrent with the depletion of liver GSH. Administration of 2MF, 1.5 hr after BSO, significantly decreased plasma cystine levels as compared to control animals that received vehicle alone. Pretreatment with BSO also resulted in increased excretion of urinary metabolites in 2MF treated animals as compared to animals receiving 2MF alone. Thus, BSO probably protects against hepatoxicity of 2MF by indirectly causing more detoxification of the reactive metabolite of 2MF, as it does not alter the distribution of unmetabolized 2MF and does not have any apparent effect on the microsomal mixed-function oxidase which mediates the activation of 2MF. The enhanced detoxification of 2MF in BSO treated animals appears independent of the depleted GSH levels; it may result from increased availability of a better alternative nucleophile (i.e. cysteine), capable of conjugating with acetyl acrolein. Acetyl acrolein (AA) appears to be the principal reactive metabolite of 2MF which binds covalently to tissues. Previous in vitro studies have shown that cysteine is a better trapping agent of AA than GSH or N-acetyl-cysteine.
在用碳 - 14（¹⁴C）标记的2 - 甲基呋喃（2MF）给药前，用丁硫氨酸亚砜胺（BSO）处理雄性Sprague - Dawley大鼠，可使¹⁴C标记的2MF代谢产物与DNA和蛋白质的共价结合显著减少，尽管标记的母体2MF的分布没有明显变化。BSO预处理还可预防2MF的肝毒性，血清谷丙转氨酶（GPT）水平降低表明了这一点。只有在2MF给药前1.5小时给予BSO预处理才有保护作用。在BSO给药后4小时和6小时给予2MF会导致2MF肝毒性的显现。用马来酸二乙酯（DEM）预先处理，会增加[¹⁴C]2MF与肝蛋白的共价结合，同时也会提高血清GPT水平。因此，通过不同机制起作用的两种不同化学物质使组织谷胱甘肽（GSH）耗竭，对2MF的共价结合和毒性产生了相反的影响。用L - 2 - 氧代噻唑烷 - 4 - 羧酸（OTZ）预处理，一种GSH生物合成的促进剂，会增加[¹⁴C]2MF的肝共价结合并增强肝毒性。然而，在腹腔注射100 mg/kg的2MF之前给予OTZ和BSO，会降低[¹⁴C]2MF的肝共价结合并降低肝毒性。2MF活性代谢产物的GSH共轭物的明显不稳定性可能解释了OTZ对2MF肝毒性的增强作用。单次皮下注射BSO会导致血浆胱氨酸水平短暂升高，同时肝GSH耗竭。与仅接受赋形剂的对照动物相比，在BSO给药后1.5小时给予2MF，可显著降低血浆胱氨酸水平。与仅接受2MF的动物相比，用BSO预处理还会导致2MF处理动物的尿代谢产物排泄增加。因此，BSO可能通过间接导致2MF活性代谢产物更多的解毒来预防2MF的肝毒性，因为它不会改变未代谢的2MF的分布，并且对介导2MF活化的微粒体混合功能氧化酶没有任何明显影响。在BSO处理的动物中2MF解毒作用的增强似乎与GSH水平的降低无关；它可能是由于能够与乙酰丙烯醛结合的更好的替代亲核试剂（即半胱氨酸）的可用性增加所致。乙酰丙烯醛（AA）似乎是2MF与组织共价结合的主要活性代谢产物。先前的体外研究表明，半胱氨酸比GSH或N - 乙酰半胱氨酸是更好的AA捕获剂。
