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ToxSci Advance Access originally published online on June 2, 2005
Toxicological Sciences 2005 87(1):146-155; doi:10.1093/toxsci/kfi211
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Phenobarbital and Phenytoin Increased Acetaminophen Hepatotoxicity Due to Inhibition of UDP-Glucuronosyltransferases in Cultured Human Hepatocytes

Seva E. Kostrubsky*,1, Jacqueline F. Sinclair{dagger},{ddagger}, Stephen C. Strom§, Sheryl Wood{dagger}, Ellen Urda*, Donna Beer Stolz, Yuan H. Wen*,2, Shaila Kulkarni* and Abdul Mutlib||

* Department of Safety Science, Pfizer Global Research and Development, Ann Arbor, Michigan 48105; {dagger} Veterans Administration Medical Center, White River Junction, Vermont 05009; {ddagger} Departments of Pharmacology/Toxicology and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03756; § Departments of Pathology and Cell Biology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261; and || Department of Pharmacokinetic, Dynamic and Metabolism, Pfizer Global Research and Development, Ann Arbor, Michigan 48105

Received March 10, 2005; accepted May 20, 2005

Here we present a preclinical model to assess drug–drug interactions due to inhibition of glucuronidation. Treatment with the antiepileptics phenobarbital (PB) or phenytoin (PH) has been associated with increased incidence of acetaminophen (APAP) hepatotoxicity in patients. In human hepatocytes, we found that the toxicity of APAP (5 mM) was increased by simultaneous treatment with phenobarbital (2 mM) or phenytoin (0.2 mM). In contrast, pretreatment with PB for 48 h prior to APAP treatment did not increase APAP toxicity unless both drugs were present simultaneously. Cells treated with APAP in combination with PB or PH experienced decreases in protein synthesis as early as 1 h, ultrastructural changes by 24 h, and release of liver enzymes by 48 h. Toxicity correlated with inhibition of APAP glucuronidation. PB or PH also inhibited APAP glucuronidation in rat and human liver microsomes and expressed human UGT1A6, 1A9, and 2B15. As with intact hepatocytes, PB and PH were neither hydroxylated nor glucuronidated, suggesting the direct inhibition of UGTs. Our findings suggest that, in multiple drug therapy, an inhibitory complex between UGT and one of the drugs can lead to decreased glucuronidation and increased systemic exposure and toxicity of a coadministered drug.

Key Words: hepatotoxicity; hepatocytes; microsomes; acetaminophen; inhibition; UGT1A; UGT2B; phenobarbital.


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