Sandberg J A, Murphey L J, Olsen G D
Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Portland, OR.
Drug Metab Dispos. 1993 Mar-Apr;21(2):390-5.
In vitro N-demethylation of cocaine (COC) was examined in five saline (SAL) and five COC-treated pregnant guinea pigs and their fetuses (60 days, term 69 days). Microsomes from maternal and fetal guinea pigs produced norcocaine (NOR), benzoylnorecgonine (BN), and benzoylecgonine (BE) when incubated with COC. The initial rate of NOR formation was (mean +/- SE) 0.69 +/- 0.09 and 0.002 +/- 0.002 nmol/min/mg in microsomes from SAL-treated dams and their fetuses, respectively. The minimal fetal N-demethylation suggests BN seen previously in vivo after chronic maternal COC administration resulted from maternal formation of NOR and subsequent maternal or fetal hydrolysis to BN. COC pretreatment increased the initial rate of NOR formation to 1.38 +/- 0.28 nmol/min/mg (p < 0.05) and increased the extent of NOR formation by 12 min (p < 0.05). There was no change in total cytochrome P-450 concentrations in the dams. COC pretreatment had no effect on fetal hepatic N-demethylation of COC or total cytochrome P-450 content. The rate of NOR production plateaued in microsomes from both treatment groups by 20 min of incubation and could be restored when the microsomes were washed, repelleted, and reincubated. This suggests a soluble metabolite of COC inhibits COC N-demethylation. Microsomes from both SAL- and COC-treated animals produced this factor in the presence of COC, but the enzyme(s) responsible for COC N-demethylation in the SAL-treated pregnant guinea pig were more sensitive to inhibition than COC-pretreated animals.
在五只生理盐水处理（SAL）的怀孕豚鼠及其胎儿（妊娠60天，足月69天）和五只可卡因（COC）处理的怀孕豚鼠及其胎儿中检测了可卡因（COC）的体外N-去甲基化。当与COC一起孵育时，来自母豚鼠和胎豚鼠的微粒体产生了去甲可卡因（NOR）、苯甲酰去甲芽子碱（BN）和苯甲酰芽子碱（BE）。来自生理盐水处理的母豚鼠及其胎儿的微粒体中NOR形成的初始速率分别为（平均值±标准误）0.69±0.09和0.002±0.002 nmol/分钟/毫克。胎儿最小的N-去甲基化表明，先前在母体长期给予COC后体内观察到的BN是由母体形成NOR并随后母体或胎儿水解为BN所致。COC预处理将NOR形成的初始速率提高到1.38±0.28 nmol/分钟/毫克（p<0.05），并使NOR形成的程度增加了12分钟（p<0.05）。母豚鼠中总细胞色素P-450浓度没有变化。COC预处理对胎儿肝脏中COC的N-去甲基化或总细胞色素P-450含量没有影响。两个处理组的微粒体在孵育20分钟时NOR产生速率达到平台期，并且当微粒体洗涤、重新沉淀并重新孵育时可以恢复。这表明COC的一种可溶性代谢产物抑制了COC的N-去甲基化。来自生理盐水处理和COC处理动物的微粒体在有COC存在的情况下都产生了这种因子，但在生理盐水处理的怀孕豚鼠中负责COC N-去甲基化的酶比COC预处理的动物对抑制更敏感。
