Fruetel J A, Sparks S E, Quistad G B, Casida J E
Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720.
Chem Res Toxicol. 1994 Jul-Aug;7(4):487-94. doi: 10.1021/tx00040a003.
Dienochlor (Pentac) (C10Cl10) has been used for 30 years as a miticide with little knowledge of its mode of action or metabolic fate except that it is quickly degraded by rats. This study examines the reactions of dienochlor with GSH and proteins as models for its metabolism and interactions with tissues. Dienochlor reacts rapidly with 1.0 mM GSH in phosphate buffer (pH 7.4) at 37 degrees C (t1/2 approximately 11 min) as analyzed by UV/visible spectroscopy and HPLC, yielding a series of more than a dozen adducts. Octachlorofulvalene (C10Cl8), a candidate intermediate, also reacts to give the same apparent products (t1/2 < 0.2 min as above); however, its intermediacy in the dienochlor reaction was not established. Isolation and MS analyses characterized two isomeric C10H2Cl(SG)5 adducts and a C10H2(SG)6 derivative; these products react further in the presence of GSH to yield two even more polar adducts. Cysteine and N-acetylcysteine also react rapidly with dienochlor whereas GSSG and several non-thiol amino acids are much less reactive. Purified GSH S-transferases (GSTs) and hemoglobins, each from six species of mammals including humans, are extensively labeled in vitro by [14C]dienochlor to form adducts separable by gel electrophoresis and HPLC. [14C]Dienochlor readily derivatizes rat liver GSTs even in cytosol and in the presence of high GSH levels. The potency of dienochlor for inhibition of GST activity is maintained or enhanced upon conversion to GSH adducts.(ABSTRACT TRUNCATED AT 250 WORDS)
二氯杀螨醇（戊氯）（C10Cl10）作为杀螨剂已使用了30年，除了知道它能被大鼠迅速降解外，人们对其作用方式或代谢命运了解甚少。本研究以二氯杀螨醇与谷胱甘肽（GSH）和蛋白质的反应作为其代谢及与组织相互作用的模型进行研究。通过紫外/可见光谱和高效液相色谱分析可知，在37摄氏度的磷酸盐缓冲液（pH 7.4）中，二氯杀螨醇与1.0 mM的GSH迅速反应（半衰期约为11分钟），生成一系列十几种以上的加合物。八氯富瓦烯（C10Cl8）作为一种可能的中间体，也会发生反应生成相同的表观产物（半衰期如上所述小于0.2分钟）；然而，其在二氯杀螨醇反应中的中间体地位尚未确定。分离和质谱分析鉴定出两种异构的C10H2Cl(SG)5加合物和一种C10H2(SG)6衍生物；这些产物在GSH存在下会进一步反应生成另外两种极性更强的加合物。半胱氨酸和N - 乙酰半胱氨酸也能与二氯杀螨醇迅速反应，而氧化型谷胱甘肽（GSSG）和几种非硫醇氨基酸的反应活性则低得多。从包括人类在内的六种哺乳动物中提取的纯化谷胱甘肽S - 转移酶（GSTs）和血红蛋白，在体外会被[14C]二氯杀螨醇大量标记，形成可通过凝胶电泳和高效液相色谱分离的加合物。即使在细胞溶质中且存在高浓度GSH的情况下，[14C]二氯杀螨醇也能轻易地使大鼠肝脏GSTs发生衍生化。二氯杀螨醇转化为GSH加合物后，其抑制GST活性的效力得以维持或增强。（摘要截选至250词）
