Jones C R, Guengerich F P, Rice J M, Lubet R A
Biological Carcinogenesis and Development Program, PRI/DynCorp, Frederick, MD 21702-1201.
Pharmacogenetics. 1992 Aug;2(4):160-72. doi: 10.1097/00008571-199208000-00003.
Male and female patas (Erythrocebus patas) and cynomolgus (Macaca fascicularis) monkeys were treated with phenobarbitone (PB) and examined for the induction of various cytochrome P450 (P450)-mediated drug metabolizing enzymes. Hydroxylation of testosterone at the 6 beta, 2 beta, and 15 beta positions, metabolites normally associated with CYP3A P450s increased 2- to 5-fold in PB-treated animals. Induction of this P450 family was confirmed by the use of polyclonal antisera directed against the human CYP3A enzymes which inhibited both induced and constitutive 6 beta- and 15 beta-hydroxylase activities in both species of monkeys. The enzymatic activities testosterone 16 beta-hydroxylation, pentoxyresorufin O-dealkylation [PROD], and benzyloxyresorufin O-dealkylation [BZROD] typically associated with the rodent CYP2B subfamily in rodents were also examined. Testosterone 16 beta-hydroxylation activity was highly induced up to 15-fold in both species of monkeys to maximal levels similar to those induced in PB-treated male rats. BZROD was similarly induced up to 10-fold in both species of monkeys, but the maximal levels of BZROD achieved were substantially lower than those obtained in PB-treated rats. Finally, PROD yielded an idiosyncratic response showing substantial induction (> 30-fold) in certain patas monkeys (4 out of 8) but minimal (< 5-fold) induction in the other patas monkeys (4 out of 8) or any of the cynomolgus monkeys (0 out of 8). Immunodetection of various cytochromes using polyclonal antisera directed against rat cytochromes confirmed the induction of CYP3A proteins as well as the induction of protein(s) immunologically cross-reactive with rat CYP2B P450s. BZROD, PROD, or testosterone 16 beta-hydroxylase activities, were not inhibited by antibody to CYP3A P450s. However, high concentrations of polyclonal antiserum directed against rat CYP2B inhibited all three activities in PB-induced patas monkeys. In contrast, this antiserum failed to inhibit the hydroxylation of testosterone at the 6 beta or 2 beta positions. Induction of the CYP2C subfamily was observed by immunochemical detection. Interestingly, induction of this subfamily appeared to be more pronounced in cynomolgus than in patas monkeys. Finally, we failed to observe significant sex-dependent differences in P450-mediated enzymatic activities in either control or induced monkeys. These results confirm the induction of a similar spectrum of P450 proteins by PB in non-human primates to that which has previously been observed in rodents.
对雄性和雌性赤猴（赤猴属）及食蟹猴（猕猴属）用苯巴比妥（PB）进行处理，并检测各种细胞色素P450（P450）介导的药物代谢酶的诱导情况。睾酮在6β、2β和15β位的羟基化产物通常与CYP3A P450相关，在PB处理的动物中增加了2至5倍。通过使用针对人CYP3A酶的多克隆抗血清，证实了该P450家族的诱导，该抗血清抑制了两种猕猴中诱导型和组成型的6β - 和15β - 羟化酶活性。还检测了通常与啮齿动物CYP2B亚家族相关的睾酮16β - 羟化、戊氧基试卤灵O - 脱烷基化[PROD]和苄氧基试卤灵O - 脱烷基化[BZROD]的酶活性。睾酮16β - 羟化活性在两种猕猴中均被高度诱导，最高可达15倍，达到与PB处理的雄性大鼠诱导的最大水平相似。BZROD在两种猕猴中同样被诱导，最高可达10倍，但达到的BZROD最大水平显著低于PB处理的大鼠。最后，PROD产生了一种特异反应，在某些赤猴（8只中的4只）中显示出大量诱导（> 30倍），而在其他赤猴（8只中的4只）或任何食蟹猴（8只中的0只）中诱导最小（< 5倍）。使用针对大鼠细胞色素的多克隆抗血清对各种细胞色素进行免疫检测，证实了CYP3A蛋白的诱导以及与大鼠CYP2B P450免疫交叉反应的蛋白的诱导。BZROD、PROD或睾酮16β - 羟化酶活性不受CYP3A P450抗体的抑制。然而，高浓度的针对大鼠CYP2B的多克隆抗血清抑制了PB诱导的赤猴中的所有三种活性。相比之下，该抗血清未能抑制睾酮在6β或2β位的羟基化。通过免疫化学检测观察到了CYP2C亚家族的诱导。有趣的是，该亚家族的诱导在食蟹猴中似乎比在赤猴中更明显。最后，我们在对照或诱导猴子中均未观察到P450介导的酶活性存在显著的性别依赖性差异。这些结果证实了PB在非人类灵长类动物中诱导的P450蛋白谱与先前在啮齿动物中观察到的相似。
