Relationship between debromination reaction of halogen compounds and organ toxicity

已知多卤化烷烃与自由基中间体发生厌氧脱卤反应，可引起肝损伤。最近发现细胞色素<b_5> (cyt.b5)可减少自由基中间体，表明cyt。<b_5>可能参与抑制多卤代烷烃的细胞毒性。阐明cyt的作用。在一个含有苯巴比妥诱导的P-450、NADPH-P-450还原酶、磷脂和NADPH的重组体系中，在好氧和厌氧条件下研究了卤代烷和1,2-二溴乙烷（DBE）的脱溴反应。用溴化物电极检测游离溴离子。在有氧条件下，cyt。<b_5>增强了氟烷和DBE的羟基化，其次是< α > -消除溴化物。ESR仅在厌氧条件下检测到自由基信号。在厌氧条件下，已知卤代烷和DBE经历一个电子还原，然后是溴的< α > -消除形成自由基中间体，随后在提供第二个电子时发生卤素的< β > -消除。Cyt。<b_5>对DBE的厌氧脱溴率有促进作用，但对< - > -位不含溴的氟烷的脱溴没有影响。因此,cyt。<b_5>似乎通过提供第二电子刺激< β > -消除卤素，可能导致自由基中间体的减少。

Polyhalogenated alkanes are known to undergo anaerobic dehalogenation reaction to radical intermediates which induce liver injury. Recently it was revealed that cytochrome <b_5> (cyt.b5) reduces radical intermediates, indicating that cyt. <b_5> may participate in preventing cytotoxicities of polyhalogenated alkanes. To clarify the effect of cyt. <b_5> on the dehalogenation reaction, debrominations of halothane and 1,2-dibromoethane(DBE) were investigated in a reconstituted system containing phenobarbital-inducible P-450, NADPH-P-450 reductase, phospholipids, and NADPH under aerobic and anaerobic conditions. Liberated bromide ion was detected by bromide electrode. Under aerobic conditions, cyt. <b_5> enhanced the hydroxylations of halothane and DBE followed by <alpha> -elimination of bromide. A radical signal was detected by ESR only under anaerobic conditions. Under anaerobic conditions, halothane and DBE are known to undergo one electron reduction followed by <alpha> -elimination of bromide to form radical intermediates, and subsequently <beta> -elimination of halogens occurs when second electron is supplied. Cyt. <b_5> stimulated the anaerobic debromination rate of DBE, but did not affect the debromination of halothane possessing no bromine at <beta> -position. Thus, cyt. <b_5> seems to stimulate <beta> -elimination of halogens by supply of second electron, presumably resulting in the decrease of radical intermediates.