Document Detail

Hepatic cytochrome P450s attenuate the cytotoxicity induced by leflunomide and its active metabolite A77 1726 in primary cultured rat hepatocytes.
MedLine Citation:
PMID:  21546349     Owner:  NLM     Status:  Publisher    
The Black Box Warning section of the US drug label for leflunomide was recently updated to include stronger warnings about potential hepatotoxicity from this novel anti- arthritis drug. Since metabolic activation is a key mechanism for drug-induced hepatotoxicity, we examined whether leflunomide and its major metabolite, A77 1726, are cytotoxic to primary rat hepatocytes and whether their toxicity is modulated by hepatic cytochrome P450s (CYPs). As measured by lactate dehydrogenase leakage, time-dependent cytotoxicity was observed at 250∼500 μM for leflunomide and 330∼500 μM for A 77 1726 within 20 h. Unexpectedly, three non-isoenzyme-specific CYP inhibitors, including SKF-525A, metyrapone and 1-aminobenzotriazole, did not reduce but remarkably enhanced the cytotoxicity of leflunomide or A77 1726. SKF-525A pretreatment notably rendered hepatocytes susceptible to as low as 15 μM leflunomide or A77 1726. Three isoenzyme-specific CYP inhibitors, including alpha-naphthoflavone, ticlopidine and ketoconazole that mainly target CYP1A, CYP2B/2C and CYP3A, respectively, also enhanced the cytotoxicity. A strong synergistic effect, similar to SKF-525A alone, was noted using a combination of all three of the isoenzyme-specific inhibitors. Hepatocytes pre-treated with the CYP inducer dexamethasone for 24 h exhibited decreased cytotoxicity to leflunomide and A77 1726. At the concentrations tested, the CYP inhibitors and inducer showed no cytotoxicity. These data demonstrate that the parent form of leflunomide and A77 1726 are more toxic to hepatocytes than their poorly-characterized metabolites, indicating that the metabolic process of leflunomide is a detoxification step rather than an initiating event leading to toxicity.
Q Shi; X Yang; J Greenhaw; Wf Salminen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-4
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  -     ISSN:  1096-0929     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-5-6     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.
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