Abstract
Dysregulations of cytochrome P450s (CYPs) 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 CYPs in thioacetamide (TAA) induced liver cirrhosis rats, and the potential counteracting effects of hepatoprotective agents, schisandra lignan extracts (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 CYPs' protein levels, which meay be ascribed to their hepatoprotective effects and direct CYPs inducing effects that have been confirmed in the healthy rats. However, the recovery of enzyme activities of most CYPs by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited a NADPH, time, and concentration dependent inactivating effects on all of the four major CYP isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA induced dysreguated CYPs.
- CYP induction
- CYP inhibition
- cytochrome P450
- liver disease
- liver injury
- liver microsomes
- mechanism-based inhibition
- Received November 2, 2011.
- Accepted January 20, 2012.
- The American Society for Pharmacology and Experimental Therapeutics