Different cytotoxicity and metabolism of doxorubicin, daunorubicin, epirubicin, esorubicin and idarubicin in cultured human and rat hepatocytes.
Both cytotoxicity and metabolism of five anthracyclines, namely doxorubicin, daunorubicin, epirubicin, esorubicin and idarubicin, were investigated in primary cultures of both rat and human adult hepatocytes and, for comparison, in a rat liver epithelial cell line. Toxicity was assessed by morphological examination and measurement of lactate dehydrogenase leakage after 24 hr of treatment. The rank order of toxicity for both rat and human hepatocytes was esorubicin greater than doxorubicin = epirubicin greater than or equal to idarubicin greater than daunorubicin, and for rat epithelial cells: esorubicin greater than or equal to epirubicin greater than idarubicin = daunorubicin = doxorubicin. Human cells were around 2-fold less sensitive than rat hepatocytes to all anthracyclines. Anthracyclines and their metabolites were analyzed by HPLC. Differences in both the percentages and routes of metabolism were demonstrated between rat and human hepatocytes. The main metabolite was the 13-dihydro-derivative (-ol derivative) in both species from daunorubicin, idarubicin and esorubicin. Glucuronides of epirubicin and epirubicinol were found only in human hepatocytes. In addition, several unidentified metabolites were detected of esorubicin, idarubicin and daunorubicin in rat hepatocytes. In human hepatocytes, only one unknown metabolite from daunorubicin and doxorubicin was found to be formed by cells from a different donor. In spite of variations between individuals, human hepatocytes generally metabolized anthracyclines more actively than did rat hepatocytes. Rat liver epithelial cells were only able to convert daunorubicin and idarubicin, the two molecules which have the best affinity for the non-specific NADPH-dependent aldoketoreductase system. Three compounds (doxorubicin, epirubicin and esorubicin) were present in large amounts in the cells as the parent drug, another (idarubicin) as the 13-dihydro-derivative. This comparative study on cytotoxicity and metabolism of five anthracyclines in rat and human hepatocyte cultures emphasises species differences and the importance of this in vitro model system for further analysis of the metabolism and effect of anthracyclines.
Le Bot
M A
MA
Laboratoire de Pharmacologie, Faculté de Médecine, Brest, France.
Bégué
J M
JM
Kernaleguen
D
D
Robert
J
J
Ratanasavanh
D
D
Airiau
J
J
Riché
C
C
Guillouzo
A
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D015251:Epirubicin / Q000378:metabolism / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015255:Idarubicin / Q000378:metabolism / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D015251:Epirubicin; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; C030851:esorubicin; D015255:Idarubicin; D003630:Daunorubicin