Decrease in hepatic CYP2C11 mRNA and increase in heme oxygenase activity after intracerebroventricular injection of...

Area of Science:

• Toxicology
• Molecular Biology
• Pharmacology

Background:

• Bacterial lipopolysaccharide (LPS) affects hepatic cytochrome P450 (CYP) isozymes.
• Intracerebroventricular (i.c.v.) LPS injection impacts CYP isozymes differently than intraperitoneal (i.p.) injection.
• CYP2C11, a male-specific isozyme, is particularly sensitive to i.c.v. LPS.

Purpose of the Study:

• To investigate the effects of i.c.v. and i.p. LPS on CYP2C11 gene expression, protein, and activity.
• To determine the impact of LPS on total P450 content and heme oxygenase (HO) activity.
• To elucidate the mechanism of LPS-induced downregulation of CYP2C11.

Main Methods:

• Rats received i.c.v. or i.p. injections of LPS or saline.
• Measurements included CYP2C11 mRNA, total P450 content, CYP2C11-dependent imipramine N-demethylase (IMND) activity, CYP2C11 protein, and HO activity.
• Analysis was performed on rat liver microsomes 10 hours post-injection.

Main Results:

• i.c.v. LPS significantly decreased CYP2C11 mRNA, total P450 content, and IMND activity.
• i.p. LPS at the same dose did not significantly affect these parameters.
• HO activity increased following both i.c.v. and i.p. LPS injections.

Conclusions:

• i.c.v. LPS down-regulates CYP2C11 expression at the transcriptional level.
• Decreased CYP2C11 mRNA and increased heme degradation contribute to reduced CYP2C11 protein and activity.
• The route of LPS administration influences its effect on hepatic CYP isozymes.