Modulation of Hepatic UGT Function by IL-6 and TNFá and its Relationship with the PXR, CAR, and AhR

Pro-inflammatory cytokines, IL-6 and TNFα, are known to suppress multiple cytochrome P450s (CYPs). Their impact on the function of UDP-glucuronosyltransferases (UGTs) has not been fully investigated. Furthermore, the mechanism of UGTs modulation by IL-6 and TNFα has not been explored although previous studies suggested that suppression of CYPs by pro-inflammatory cytokines may be via down-regulation of the nuclear receptors.

In this study, we examined the effects of IL-6 and TNFα on the function of UGT1A1, UGT1A4, UGT1A9, and UGT2B7, using estradiol-3-glucuronidation (UGT1A1), lamotrigine-N2-glucuronidation (UGT1A4), propofol-glucuronidation (UGT1A9), and zidovudine-glucuronidation (UGT2B7) as probe reactions. Hepatocytes in sandwich culture were treated with different concentrations of IL-6 or TNFα for 72 h. At the end of the treatment, UGT activities were assessed with individual probe substrates. IL-6 and TNFα showed significant and concentration-dependent suppression on UGT2B7-dependent zidovudine glucuronidation. In a concentration range of 0.2 -20 ng/mL, IL-6 decreased zidovudine glucuronidation by up to 60%, and TNFα decreased zidovudine glucuronidation by up to 48%. IL-6 at 20 ng/mL also showed significant suppression on UGT1A9-dependent propofol glucuronidation (decreased by 40%). For estradiol-3-glucuronidation and lamotrigine–N2-glucuronidation, no obvious modulation was observed. The considerable suppression of IL-6 and TNFα on zidovidine glucuronidation suggests the possibility that therapeutic proteins, which modulate IL-6 or TNFα function, may affect UGT2B7-mediated small molecule drug metabolism.

We also evaluated the expression of PXR, CAR, and AhR in the hepatocytes after 72-h direct exposure to different concentrations of IL-6 and TNFα. The results showed that IL-6 and TNFα modulated the expression of PXR, CAR, and AhR differently. TNFα exhibited small but significant suppression on AhR but had no effects on the expression of PXR and CAR. IL-6 (at higher concentrations), on the other hand, significantly decreased the expression of PXR and CAR, but had no obvious remarkable impact on the expression of AhR. These results suggest that the mechanisms of UGT-suppression by IL-6 and TNFα are different. Down-regulation of PXR and CAR is likely one of the mechanisms for UGT- suppression by high concentrations of IL-6, whereas AhR may be involved in TNFα-mediated UGT-suppression.