Abstract
Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.
Footnotes
This work was supported by the National Natural Science Foundation of China [Grants 91029746, 30801422]; the Program for New Century Excellent Talents in University of China [Grant NCET-09-0770]; and a Foundation for the Author of National Excellent Doctoral Dissertation of China [Grant 200979].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- TAA
- thioacetamide
- DME
- drug-metabolizing enzyme
- P450
- cytochrome P450
- SLE
- schisandra lignans extract
- DDB
- dimethyl diphenyl bicarboxylate
- ALT
- alanine aminotransferase
- AST
- aspartate aminotransferase
- GGT
- γ-glutamyl transferase
- ALP
- alkaline phosphatase
- Tbil
- total bilirubin
- RLM
- rat liver microsomes
- PVDF
- polyvinylidene fluoride
- UGT
- UDP-glucuronosyltransferase.
- Received October 27, 2011.
- Accepted January 20, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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