Effect of SPG/indomethacin treatment on sepsis, interleukin-6 production, and expression of hepatic cytochrome P450 isoforms in differing strains of mice.

We previously reported that a combination of beta-glucan and indomethacin (IND), a non-steroidal anti-inflammatory drug, was lethal to mice. This lethality was strongly related to translocation of enterobacterial flora to various organs and the development of a systemic inflammation. In this study, we examined expression of microsomal cytochrome P450 (CYP), a drug-metabolizing enzyme mostly found in the liver. Normal ICR mice and endotoxin-low responder C3H/HeJ mice were employed to assess effects of endotoxin on impairment of CYP. In the ICR mice, CYP3A11 expression was decreased by beta-glucan or IND. In the early stage of beta-glucan + IND-treatment, 3A11 expression decreased more significantly; when shock was induced, CYP was dramatically decreased. 3A11 expression was also decreased in C3H/HeJ mice, but the effect was milder. In contrast, in both strains, CYP2E1 expression did not vary due to beta-glucan or IND, but decreased during sepsis. To clarify the molecular mechanisms of induced sepsis in C3H/HeJ mice, the reactivity of other pathogen-associated molecular patterns (PAMPs) was assessed. Those studies showed cooperative effects between Pam(3)CSK(4) (Pam(3)) and CpG ODN (CpG-oligodeoxynucleotide) on the induction of IL-6 synthesis by C3H/HeJ spleen cells. The findings here suggest that the beta-glucan + IND combination influenced hepatic cytochrome P450 expression, particularly in the late stage of sepsis. The results also indicate that this change may be associated with not only endotoxin but other PAMPs as well, and could be affected by the integrity of a host's drug metabolism function.