Induction of cytochrome P4503A by taxol in primary cultures of human hepatocytes.
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 microM) resulted in increases in immunoreactive CYP3A. In four of the cultures, treatment of hepatocytes with the lowest concentration of Taxol tested (0.2 microM) resulted in approximately two-fold increases in CYP3A. In the other culture, however, a six-fold increase in CYP3A was observed at 0.2 microM. 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 hepatocytes. The clinical significance of these findings is discussed.
Veterans Administration Medical Center, White River Junction, Vermont, 05009, USA.
V E
VE
Kostrubsky
L D
LD
Lewis
S C
SC
Strom
S G
SG
Wood
E G
EG
Schuetz
J D
JD
Schuetz
P R
PR
Sinclair
S A
SA
Wrighton
J F
JF
Sinclair
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects; D012293:Rifampin / Q000494:pharmacology
D012333:RNA, Messenger; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017239:Paclitaxel; D012293:Rifampin; D010634:Phenobarbital