Comparison of four modulators of drug metabolism as protectants against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the female rat and in hepatocytes in vitro.
OBJECTIVE
Yondelis (ET-743), a tetrahydroisoquinoline alkaloid isolated from a marine tunicate, is a novel drug with demonstrated anticancer activity in early clinical trials against sarcoma, breast and ovarian carcinoma. Yondelis has myelotoxic and hepatotoxic side effects, the latter reflected by reversible transaminitis and cholangitis. In the female rat pretreatment with high-dose dexamethasone has been shown to abrogate yondelis-mediated hepatotoxicity, an effect tentatively linked to its ability to induce cytochrome P450 CYP3A isoenzymes, which metabolize yondelis. Here we tested the hypothesis that pretreatment of rats with modulators of hepatic drug metabolism, beta-naphthoflavone, phenobarbitone or N-acetylcysteine, protect rat livers against the effects of yondelis.


METHODS
Female rats received yondelis (40 microg/kg intravenously) and liver damage in vivo was assessed in terms of changes in plasma levels of bilirubin, alkaline phosphatase (ALP) and aspartate aminotransferase (AST) and by histopathology. In order to investigate yondelis toxicity in vitro, hepatocytes isolated from untreated rats or from rats pretreated with dexamethasone, beta-naphthoflavone or phenobarbitone were maintained in culture and exposed to yondelis.


RESULTS
Pretreatment with beta-naphthoflavone and phenobarbitone ameliorated yondelis-mediated hepatotoxicity in vivo. The former abrogated plasma indicators on day 3, but hardly on day 6, and the latter suppressed elevation of bilirubin, but not of ALP or AST. Pretreatment with N-acetylcysteine did not protect from, but slightly exacerbated, yondelis-induced liver changes. Hepatocytes from naive animals or from pretreated rats did not differ in their susceptibility towards yondelis-induced cytotoxicity in vitro. Nor did inclusion of N-acetylcysteine (1 m M) in the cellular incubation medium affect yondelis-induced hepatocytotoxicity.


CONCLUSIONS
The results suggest that certain inducers of cytochrome P450 enzymes such as dexamethasone and beta-naphthoflavone can protect rat liver against the unwanted effects of yondelis, but such protection cannot be mimicked in in vitro experiments using liver cells in culture.
Donald
Sarah
S
Department of Oncology, University of Leicester, LRI, 5th floor RKCSB, Leicester, LE2 7LX, UK.
Verschoyle
Richard D
RD
Greaves
Peter
P
Orr
Samantha
S
Jimeno
Jose
J
Gescher
Andreas J
AJ
D000111:Acetylcysteine / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D003907:Dexamethasone / Q000494:pharmacology; D004149:Dioxoles / Q000633:toxicity*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008658:Inactivation, Metabolic; D007546:Isoquinolines / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D019324:beta-Naphthoflavone / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D000077606:Trabectedin; D000111:Acetylcysteine; D010634:Phenobarbital