Beck M J, McLellan C, Lightle R L, Philbert M A, Harris C
Toxicology Program, Department of Environmental Health Sciences, The University of Michigan, Ann Arbor, Michigan 48109-2029, USA.
Toxicol Sci. 2001 Jul;62(1):92-102. doi: 10.1093/toxsci/62.1.92.
Glutathione (GSH), cysteine, and other low-molecular-weight thiols (LMWT) play a vital role in the detoxication of xenobiotics and endogenous chemicals. Differential alterations of LMWT status in various cell types of the developing embryo may underlie cell-specific sensitivity or resistance to xenobiotics and contribute to embryotoxicity. This study describes the spatial and temporal distribution of LMWTs in rat conceptuses and alterations produced by the non-teratogenic GSH modulator, acetaminophen (APAP). Pregnant female rats were given 125, 250, or 500 mg/kg APAP (po) on gestational day 9. Conceptal LMWT was localized histochemically using mercury orange in cryosections, and GSH and cysteine concentrations were measured by HPLC analysis. Mercury orange histofluorescence revealed a non-uniform distribution of LMWT in untreated conceptal tissues, with strongest staining observed in the ectoplacental cone (EPC), visceral yolk sac (VYS), and embryonic heart. Less intense staining was observed in the neuroepithelium. Following treatment with APAP, tissue-associated LMWT decreased dramatically except in the EPC, while exocoelomic fluid LMWT, and LMWT within embryonic lumens, increased. Exposure to 250 mg/kg APAP decreased embryonic GSH after 6 and 24 h by 46% and 38%, respectively. Acetaminophen (500 mg/kg) decreased embryonic and VYS cysteine content by 54% and 83%, respectively, after 24 h. Acetaminophen alters the spatial distribution of LMWT in rat conceptuses, particularly with respect to cysteine. The mobilization of cysteine following chemical insult may influence the ability of conceptal cells to maintain normal GSH status due to reduced availability of cysteine for de novo GSH synthesis.
谷胱甘肽（GSH）、半胱氨酸及其他低分子量硫醇（LMWT）在异生物素和内源性化学物质的解毒过程中发挥着至关重要的作用。发育中胚胎的各种细胞类型中LMWT状态的差异改变可能是细胞对异生物素具有特异性敏感性或抗性的基础，并导致胚胎毒性。本研究描述了LMWT在大鼠孕体中的时空分布以及由非致畸性GSH调节剂对乙酰氨基酚（APAP）所产生的改变。在妊娠第9天，给怀孕的雌性大鼠经口给予125、250或500 mg/kg的APAP。使用汞橙对冷冻切片进行组织化学定位，以确定孕体中的LMWT，并通过高效液相色谱分析测定GSH和半胱氨酸的浓度。汞橙组织荧光显示，在未处理的孕体组织中，LMWT分布不均匀，在外胎盘锥（EPC）、脏卵黄囊（VYS）和胚胎心脏中观察到最强的染色。在神经上皮中观察到的染色较弱。用APAP处理后，除EPC外，组织相关的LMWT显著减少，而胚外体腔液LMWT以及胚胎腔内的LMWT增加。暴露于250 mg/kg的APAP后，6小时和24小时胚胎GSH分别下降了46%和38%。24小时后，对乙酰氨基酚（500 mg/kg）使胚胎和VYS中的半胱氨酸含量分别下降了54%和83%。对乙酰氨基酚改变了大鼠孕体中LMWT的空间分布，尤其是半胱氨酸。化学损伤后半胱氨酸的动员可能会影响孕体细胞维持正常GSH状态的能力，因为用于从头合成GSH的半胱氨酸可用性降低。
