REGULATION OF URIDINE-DIPHOSPHATE GLUCURONOSYLTRANSFERASE DURING THE ACUTE-PHASE RESPONSE

The acute-phase response is associated with profound effects on oxidat ive drug metabolism. However, the effects on glucuronidation are poorl y characterized. The aim of the present study was to determine the rol e of mediators of the acute-phase response in the regulation of hepati c uridine diphosphate glucuronosyltransferase (UGT) expression. Family 1 and family 2 UGT isoforms were studied in turpentine-injected rats and in primary hepatocyte cultures exposed to cytokines and/or dexamet hasone. In the in vivo model, glucuronidation of p-nitrophenol was una ffected, while testosterone glucuronidation was reduced to 65% of cont rol (P < 0.01). In contrast, the mRNA level of UGT11 (which metaboliz es bilirubin, not phenols) was depressed to 16% of control (P < 0.002) , while the mRNA level of UGT2B3 (which metabolizes testosterone) was reduced to 53% (P < 0.05). In primary hepatocyte culture, dexamethason e treatment resulted in a 3.4-fold induction of UGT11 mRNA levels (P < 0.001) but only a 1.5-fold induction of UGT2B3 (P = 0.1). Interleuki n-6 in the presence of dexamethasone resulted in a marked dose-depende nt suppression of both UGT11 and UGT2B3, although to different degree s. Interleukin-1 had no effect on UGT mRNA levels. Thus, inflammatory mediators, such as cytokines and glucocorticoids, may be important det erminants of both oxidative and conjugative drug metabolism by the liv er.