Induction of cytochrome P4503A by Taxol in primary cultures of human hepatocytes

被引:68
作者
Kostrubsky, VE
Lewis, LD
Strom, SC
Wood, SG
Schuetz, EG
Schuetz, JD
Sinclair, PR
Wrighton, SA
Sinclair, JF [1 ]
机构
[1] Vet Adm Med Ctr, Res 151, White River Junction, VT 05009 USA
[2] Dartmouth Med Sch, Dept Pharmacol Toxicol, Hanover, NH 03756 USA
[3] Dartmouth Med Sch, Dept Biochem, Hanover, NH 03756 USA
[4] Dartmouth Med Sch, Dept Med, Hanover, NH 03756 USA
[5] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA
[6] St Jude Childrens Res Hosp, Memphis, TN 38138 USA
[7] Lilly Res Labs, Dept Drug Disposit, Indianapolis, IN 46285 USA
关键词
Taxol; CYP3A; CYP3A4; mRNA; human; hepatocytes;
D O I
10.1006/abbi.1998.0730
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In primary cultures of human hepatocytes, paclitaxel (Taxol), at pharmacological concentrations, was demonstrated to induce immunoreactive cytochrome P4503A (CYP3A), The magnitude of the inductive response of the hepatocytes to Taxol varied in five separate cultures. In general, exposure to increasing concentrations of Taxol (0.2 to 10 mu M) resulted in increases in immunoreactive CYP3A. In four of the cultures, treatment of hepatocytes with the lowest concentration of Taxol tested (0.2 mu M) resulted in approximately two-fold increases in CYP3A. In the other culture, however, a six-fold increase in CYP3A was observed at 0.2 mu M. Taxol was almost as effective as rifampicin in inducing CYP3A in two of the cultures, but less effective than rifampicin in two other cultures. CYP3A4 mRNA was increased by Taxol, Increases in CYP3A4 mRNA correlated with increases in the levels of immunoreactive CYP3A. These results demonstrate that Taxol is a potent inducer of CYP3A in human hepatocyte, The clinical significance of these findings is discussed. (C) 1998 Academic Press.
引用
收藏
页码:131 / 136
页数:6
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