Regulation of uridine diphosphate glucuronosyltransferase during the acute-phase response.
The acute-phase response is associated with profound effects on oxidative drug metabolism. However, the effects on glucuronidation are poorly characterized. The aim of the present study was to determine the role of mediators of the acute-phase response in the regulation of hepatic 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 dexamethasone. In the in vivo model, glucuronidation of p-nitrophenol was unaffected, while testosterone glucuronidation was reduced to 65% of control (P<0.01). In contrast, the mRNA level of UGT1*1 (which metabolizes 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, dexamethasone treatment resulted in a 3.4-fold induction of UGT1*1 mRNA levels (P<0.001) but only a 1.5-fold induction of UGT2B3 (P=0.1). Interleukin-6 in the presence of dexamethasone resulted in a marked dose-dependent suppression of both UGT1*1 and UGT2B3, although to different degrees. Interleukin-1 had no effect on UGT mRNA levels. Thus, inflammatory mediators, such as cytokines and glucocorticoids, may be important determinants of both oxidative and conjugative drug metabolism by the liver.
Strasser
S I
SI
Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria, Australia.
Mashford
M L
ML
Desmond
P V
PV
D000210:Acute-Phase Reaction / Q000201:enzymology*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000201:enzymology* / Q000276:immunology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D014453:Glucuronosyltransferase