Yan C C, Huxtable R J
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724.
Toxicol Appl Pharmacol. 1995 Jan;130(1):132-9. doi: 10.1006/taap.1995.1017.
The influence of GSH concentration on metabolism of monocrotaline was examined in the isolated, perfused rat liver. Chloroethanol (0.37 mmol/kg), diethyl maleate (5.6 mmol/kg), and buthionine sulfoximine (72.9 mmol/kg) given in vivo reduced hepatic GSH from 3.7 mumol/g wet weight to 1.5, 0.6 and 0.9 mumol/g, respectively. Livers were then perfused in vitro for 1 hr with monocrotaline (0.5 mM). GSH depletion had no effect on the total release of pyrrolic metabolites of monocrotaline. Depletion, however, markedly affected the pattern of pyrrole release. Biliary release of 7-glutathionyl-6,7-dihydro-1-hydroxy-methyl-5H-pyrrolizine (GSDHP) was reduced by up to 72%. Pretreatment with diethyl maleate or buthionine sulfoximine increased the level of protein-bound pyrroles in the liver by 107 and 84%, respectively. Such pyrroles are probably responsible for liver toxicity. GSH depletion also led to a doubling of dehydromonocrotaline release into the perfusate. This metabolite is probably responsible for the extrahepatic toxicity of monocrotaline. Release into perfusate of the relatively nontoxic metabolite, 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) was correspondingly decreased. Hepatic GSH content was increased to 4.4 mumol/g by pretreatment with oxo-4-thiazolidine carboxylate (4.76 mmol/kg). This agent increased total pyrrolic metabolites by 54%. Biliary release of GSDHP and perfusate release of dehydromonocrotaline and DHP were all increased. Thus, hepatic GSH levels regulate the metabolism of monocrotaline and dehydromonocrotaline and, consequently, the hepatic and extrahepatic toxicity of monocrotaline. GSH depletion leads to a switch from the biliary release of the midly toxic GSDHP to the perfusate release of the highly toxic dehydromonocrotaline. GSH depletion also permits more dehydromonocrotaline in the liver to become available for macromolecular alkylation. These findings suggest that nutritional intake of sulfur-containing amino acids can influence the severity of pyrrolizidine poisoning.
在离体灌注大鼠肝脏中研究了谷胱甘肽（GSH）浓度对野百合碱代谢的影响。体内给予氯乙醇（0.37 mmol/kg）、马来酸二乙酯（5.6 mmol/kg）和丁硫氨酸亚砜胺（72.9 mmol/kg）后，肝脏中GSH含量从3.7 μmol/g湿重分别降至1.5、0.6和0.9 μmol/g。然后将肝脏在体外以野百合碱（0.5 mM）灌注1小时。GSH耗竭对野百合碱吡咯代谢产物的总释放量没有影响。然而，GSH耗竭显著影响吡咯的释放模式。7-谷胱甘肽基-6,7-二氢-1-羟甲基-5H-吡咯嗪（GSDHP）的胆汁释放量减少了72%。用马来酸二乙酯或丁硫氨酸亚砜胺预处理后，肝脏中与蛋白质结合的吡咯水平分别增加了107%和84%。这些吡咯可能是肝脏毒性的原因。GSH耗竭还导致灌注液中脱氢野百合碱的释放量增加了一倍。这种代谢产物可能是野百合碱肝外毒性的原因。相对无毒的代谢产物6,7-二氢-7-羟基-1-羟甲基-5H-吡咯嗪（DHP）向灌注液中的释放相应减少。用氧代-4-噻唑烷羧酸盐（4.76 mmol/kg）预处理后，肝脏GSH含量增加至4.4 μmol/g。该试剂使吡咯代谢产物总量增加了54%。GSDHP的胆汁释放以及脱氢野百合碱和DHP向灌注液中的释放均增加。因此，肝脏GSH水平调节野百合碱和脱氢野百合碱的代谢，从而调节野百合碱的肝脏和肝外毒性。GSH耗竭导致从低毒GSDHP的胆汁释放转变为高毒脱氢野百合碱向灌注液中的释放。GSH耗竭还使肝脏中更多的脱氢野百合碱可用于大分子烷基化。这些发现表明含硫氨基酸的营养摄入可影响吡咯烷中毒的严重程度。
