In vitro metabolism of 2,2′,3,4′,5,5′,6-heptachlorobiphenyl (CB187) by liver microsomes from rats, hamsters and guinea pigs
In vitro metabolism of 2,2′,3,4′,5,5′,6-heptachlorobiphenyl (CB187) by liver microsomes from rats, hamsters and guinea pigs
复制标题
DOI：
10.1080/00498250500087507
复制
发表时间：
2005-04-01
期刊：
影响因子：
1.8
通讯作者：
Koga, N
中科院分区：
文献类型：
--
作者：
Ohta, C;Haraguchi, K;Koga, N
用大鼠、仓鼠和豚鼠的肝微粒体研究了2，2‘，3，4’，5，5‘，6-七氯联苯(CB187)的代谢，并考察了细胞色素P450(CYP)诱导剂苯巴比妥(PB)和3-甲基胆蒽(MC)对其代谢的影响。在未经处理的动物体内，豚鼠肝微粒体形成了3种代谢物，分别是4‘-羟基2，2’，3，5，5‘，6-六氯联苯(M-1)，4’-羟基-2，2‘，3，3’，5，5‘，6-七氯苯(M-2)和4-羟基-CB187(M-3)。M-1、M-2和M-3的形成速率分别为18.1、36.6、14.7pmolh(-1)mg蛋白(-1)。未处理的大鼠和仓鼠的肝微粒体不形成CB187代谢物。在豚鼠中，PB处理使M-1和M-2显著增加，分别是未处理动物的1.9倍和3.4倍，但不影响M-3的形成。在大鼠，PB可引起M-2和M-3的出现，其形成率分别为87.1pmolh(-1)和13.7pmolh(-1)mg蛋白(-1)，但未观察到M-1。在仓鼠中，PB处理仅以29.4pmolh(-1)mg蛋白(-1)的速率形成M-2。另一方面，MC处理的豚鼠将M-1和M-2的形成减少到不到未处理动物的50%。大鼠和仓鼠的MC微体不产生代谢产物。用三百亩L抗血清与PB处理的豚鼠肝微粒体预温育，对M-1的抑制率为80%，对M-2和M-3的抑制率为100%。这些结果表明，铅诱导的细胞色素P450的形成，特别是豚鼠、大鼠和仓鼠的细胞色素P450在CB187代谢中起重要作用。豚鼠的CB187代谢可能是通过3，4-或3‘，4’-氧化物的形成和随后的NIH-位移或脱氯来进行的。
The metabolism of 2,2',3,4',5,5',6-heptachlorobiphenyl (heptaCB) (CB187) was studied using liver microsomes of rats, hamsters and guinea pigs, and the effect of cytochrome P450 (CYP) inducers, phenobarbital (PB) and 3-methylcholanthrene ( MC), was also investigated. In untreated animals, guinea pig liver microsomes formed three metabolites which were deduced to be 4'-hydroxy2,2',3,5,5',6-hexachlorobiphenyl (M-1), 4'-hydroxy-2,2',3,3',5,5',6-heptaCB (M-2) and 4-OH-CB187 (M-3) from the comparison of GC/MS data with some synthetic authentic samples. The formation rate of M-1, M-2 and M-3 was 18.1, 36.6, 14.7 pmol h(-1) mg protein(-1), respectively. Liver microsomes of untreated rats and hamsters did not form CB187 metabolites. In guinea pigs, PB-treatment increased M-1 and M-2 significantly to 1.9- and 3.4-fold of untreated animals but did not affect the formation of M-3. In rats, PB-treatment resulted in the appearance of M-2 and M-3 with formation rates of 87.1 and 13.7 pmol h(-1) mg protein(-1), respectively, but M-1 was not observed. In hamsters, PB-treatment formed only M-2 at a rate of 29.4 pmol h(-1) mg protein(-1). On the other hand, MC-treatment of guinea pigs decreased the formation of M-1 and M-2 to less than 50% of untreated animals. MC-microsomes of rats and hamsters produced no metabolites. Preincubation of antiserum (300 mu l) against guinea pig CYP2B18 with liver microsomes of PB-treated guinea pigs produced 80% inhibition of M-1 and the complete inhibition of M-2 and M-3. These results suggest that PB-inducible CYP forms, especially guinea pig CYP2B18, rat CYP2B1 and hamster CYP2B, are important in CB187 metabolism and that CB187 metabolism in guinea pigs may proceed via the formation of 3,4- or 3',4'- oxide and subsequent NIH-shift or dechlorination.