Effects of microsomal enzyme inducers upon UDP-glucuronic acid concentration and UDP-glucuronosyltransferase activity in the rat intestine and liver.
This study was conducted to evaluate UDP-glucuronosyl-transferase (UDP-GT) activity, UDP-glucuronic acid (UDP-GA) concentration, and UDP-glucose (UDPG) concentration in the rat intestine and liver following oral administration of butylated hydroxyanisole (BHA), benzo[a]pyrene (BaP), 3-methylcholanthrene (3MC), phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or trans-stilbene oxide (TSO). Microsomal UDP-GT activity was assayed in vitro with acetaminophen (AA), harmol (HA), and 1-naphthol (NA) as the aglycones. Intestinal HA and AA glucuronidation were enhanced by BHA, BaP, and TSO, whereas 3MC, PB, PCN, and TCDD augmented hepatic HA-glucuronide formation and BHA, PB, PCN, TCDD, and TSO significantly increased hepatic AA glucuronidation. All inducing agents except PB and PCN markedly increased both intestinal and hepatic NA glucuronidation. PB, PCN, and TCDD paradoxically decreased intestinal glucuronidation of AA and HA. A similar effect upon hepatic glucuronidation was not observed with any of the agents studied. Hepatic UDP-GA concentration was increased significantly by all inducers studied except PCN and TCDD, whereas hepatic UDPG concentration was increased only by BHA. In the intestine, significant increases in UDP-GA concentration were produced only by BHA and BaP, which also elevated intestinal UDPG. These results demonstrate that microsomal enzyme inducers evoke different effects upon intestinal and hepatic glucuronidation. These differences are manifested with regard to induced changes in UDP-GT activity as well as treatment-induced alterations in UDP-GA content. Thus, the present study further underscores the marked variance of intestinal and hepatic xenobiotic glucuronidation.
Goon
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Klaassen
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D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D004790:Enzyme Induction; D005964:Glucosyltransferases / Q000032:analysis*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D066298:In Vitro Techniques; D007422:Intestines / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D014535:Uridine Diphosphate Glucuronic Acid / Q000032:analysis*
D002250:Carbon Radioisotopes; D014535:Uridine Diphosphate Glucuronic Acid; D005964:Glucosyltransferases; D014453:Glucuronosyltransferase; C059055:N-acetylglucosaminyldiphosphoundecaprenol glucosyltransferase