Effect of Taxol on cytochrome P450 3A and acetaminophen toxicity in cultured rat hepatocytes: comparison to dexamethasone.
The purpose of this study was to determine if Taxol induced CYP3A in primary cultures of rat hepatocytes and, if so, whether induction of CYP3A would increase acetaminophen toxicity. Taxol caused a concentration-dependent increase in the amount of immunoreactive CYP3A and in the steady-state levels of CYP3A1/DEX but not CYP3A2 mRNA. Similar concentration-dependent increases in toxicity as measured by a decrease in protein synthesis were observed after exposure of cells to acetaminophen for 7 hr whether cells were pretreated with Taxol or dexamethasone. Increased release of lactate dehydrogenase occured after 24 hr exposure to acetaminophen, with no further decreases in protein synthesis than those observed at 7 hr. Increases in acetaminophen toxicity correlated with increased covalent binding of acetaminophen to cellular proteins. Triacetyloleandomycin, a selective inhibitor of CYP3A, completely protected the cells against acetaminophen toxicity in both Taxol- and dexamethasone-pretreated cells and prevented the increase in covalent binding of acetaminophen to cellular proteins. These results demonstrate that Taxol, like dexamethasone, induces CYP3A and that increases in this P450 are responsible for increased acetaminophen toxicity.
Kostrubsky
V E
VE
Veterans Administration Medical Center, White River Junction, Vermont 05009, USA.
Lewis
L D
LD
Wood
S G
SG
Sinclair
P R
PR
Wrighton
S A
SA
Sinclair
J F
JF
D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D014217:Troleandomycin / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D000082:Acetaminophen; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017239:Paclitaxel