第一章：細胞色素P450同

The role of cytochrome P450 3A in the metabolism of Territrem B and C in Liver microsomes from 14-week-old Wistar rats；The effect of sex hormone and xenobiotics on CYP450 3A1/2 expression in rat hepatoma cells McA-RH8994 and McA-RH7777

陳佩君(Pei-Chun Chen)

指導教授 ： 彭福佐

國立臺灣大學/醫學院/毒理學研究所/碩士(2004年)

https://doi.org/10.6342/NTU.2004.00969

摘要

第一章
土震素為土麴菌編號23-1 ( Aspergillus terreus 23-1 )經米培養，由氯仿萃取分離純化出土震素A、B、C (TRA、TRB、TRC) 三種震顫性黴菌毒素，過去研究指出土震素A可經由成熟雄性大鼠肝臟微粒體代謝生成MA1、MAX以及MA2，而雌性大鼠僅能代謝至MA1，然後由不同細胞色素P450同

關鍵字

土震素 ； 性荷爾蒙 ； 細胞色素P450 ； 免疫抑制劑 ； 化學抑制劑

並列摘要

第一章
Territrem is a tremogenic mycotoxin isolated from the chloroform extracts of rice culture of Aspergillus terreus 23-1. The previous study showed that three metabolites MA1, MAX and MA2 of territrem A (TRA) were formed in male rats, and gender difference in TRA metabolism of Wistar rats from that only MA1 formation was formed in female rats. Further study of cytochrome P450 involvement TRA metabolism suggested CYP3A1 is mainly responsible for MA1 formation and CYP3A2 is responsible for MA1, MAX, and MA2 formation. It has been reported that four metabolites of territrem B (TRB), designated as MB1, MB2, MB3, and MB4 and one metabolite of territrm C (TRC), designated as MB1, were formed from liver microsomes of both sexs Wistar rats. The metabolism of TRB and TRC related to gender difference and CYP450 family involved were not investigated.
To investigate which cytochrome P450 isoforms were involved in TRB and TRC metabolism, four CYP450 isoform-specific inhibitors (
furafylline, orphenadrine, cimetidine, and troleandomycin) and antibodies against CYP1A2, CYP2B1, CYP2C11, or CYP3A2 were used. The gender difference in TRB and TRC metabolism in liver microsomes of 14-week-old male and female Wistar rats were also investigated. The following results indicated that (1) Metabolism of TRB to MB2, and metabolism of TRC to MB1 were observed in both sexes. The amounts of MB2, MB4, and MB1 formed were higher in male rats.(2) Formation of MB2, MB4, and MB1 was markedly inhibited by cimetidine and troleandomycin, but less by furafylline and orphenadrine. (3) Anti-CYP3A2 antibody markedly inhibited MB2, MB4, and MB1 formation, while antibodies against CYP1A1, CYP2B1, or CYP2C11 had little effect, and (4) Of the seven tested supersomes from baculovirus-transformed insect cells expressing rat CYP450 isoforms ( 1A1, 1A2, 2B1, 2C11, 2C12, 3A1, and 3A2), only those expressing CYP3A1 and CYP3A2 metabolized TRB and TRC. (5) The amounts of MB2, MB4, and MB1 were related to the 6

並列關鍵字

Territrem ； PB ； DHT ； 6b-estradiol ； PXR/RXRa ； supersomes ； CYP 3A1/2 ； GR ； DEX

參考文獻

Alvares, A. P. and Mannering, G. J. 1970. Two-substrate kinetics of drug-metabolizing enzyme systems of hepatic microsomes. Mol. Pharmacol. 6:206-212.

Birnbaum, L. S., and Baird, D. M. (1978) Induction of hepatic mixed function oxidases in senescent rodents. Exp. Gerontol. 13: 299-303.

Chen, J. W., Luo, Y. L., Hwang, M. J., Peng, F. C., and Ling, K. H. 1999. Territrem B, a tremorgenic mycotoxin that inhibits acetylcholinesterase with a noncovalent yet irreversible binding mechanism. J. Biol. Chem. 274:34916-34923.

Guengerich, F. P., Wang, P., and Davidson, N. K. 1982. Estimation of isozymes of microsomal cytochrome P-450 in rats, rabbits, and humans using immunochemical staining coupled with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biochemistry 21:1698-1706.

Halpert, J. R. 1995. Strutural basis of selective cytochrome P450 inhibition. Ann. Rev. Pharmacol.Toxicol. 35:29-53.