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

We previously reported (Arch. Toxcol. 1998, 72, 492-498) that the different ial decrease in the levels of hepatic cytochrome P450 (CYP) isozymes in rat s was observed 24 hr after intracerebroventricular (icv) injection of bacte rial lipopolysaccharide (LPS) at the dose ineffective (0.1 mu g) when injec ted intraperitoneally (ip). Among CYP isozymes we examined, the male specif ic CYP isozyme, CYP2C11 was most severely affected by icy injection of LPS. In this study, we examined the gene expression of CYP2C11, the total P450 contents, the CYP2C11-dependent activity of imipramine N-demethylase (IMND) and protein of CYP2C11 10 hr after icy or ip injections of LPS. Intracereb roventricular injection of LPS significantly decreased the level of CYP2C11 mRNA (to 63% of saline icy control), the total P450 contents (to 70% of sa line icy control), the IMND activity (to 74% of saline icy control), but no t protein of CYP2C11 in rat liver. In contrast, ip injection of LPS at the same dose as icy did not significantly affect these parameters. Since CYP i s a heme protein, we also measured the activity of heme oxygenase (HO) usin g the same rat liver microsomes. The HO activity was increased to 166% by i cy injection of LPS and 135% by ip injection of LPS compared to correspondi ng saline control. It is suggested that icy injection of LPS down-regulates the expression of CYP2C11 at transcriptional level and that both the decre ase in CYP2C11 mRNA and the increase in heme degradation may be involved in the decreased level of protein and activity of CYP2C11 by icy injection of LPS in rat liver.