DIFFERENTIAL EFFECT OF HYPOPHYSECTOMY AND GROWTH-HORMONE TREATMENT ONHEPATIC GLUCURONOSYLTRANSFERASES IN MALE-RATS - EVIDENCE FOR AN ACTION AT A PRETRANSLATIONAL LEVEL FOR ISOFORMS GLUCURONIDATING BILIRUBIN

The influence of growth hormone (GH) on 4-nitrophenol, bilirubin, test osterone, androsterone and estrone glucuronidation activities was stud ied in fully activated male rat hepatic microsomes. Sham operated and hypophysectomized animals were injected with two different dosages of GH, mimicking either the male or female GH secretion pattern. Half the animals received thyroxine and cortisol in concentrations chosen to c ompensate for the lack of thyroid hormones and glucocorticoids in hypo physectomized rats. GH induced a decrease in several glucuronidation a ctivities: bilirubin glucuronidation in both sham-operated and cortiso l/ thyroxine-treated hypophysectomized rats in a dose-dependent manner , testosterone glucuronidation in hypophysectomized animals, and andro sterone and estrone glucuronidation in cortisol/thyroxin-treated hypop hysectomized rats. 4-nitrophenol glucuronidation was not affected by G H treatment. A hypothetical ''feminizing'' effect of GH (due to an alm ost continuous secretion) could not be invoked to explain these result s, contrary to what has been observed elsewhere for other hepatic enzy me activities. Hypophysectomy altered all the activities tested, with bilirubin the most modified (a 200% enhancement). Restoration of contr ol values was achieved in hypophysectomized animals with cortisol/thyr oxine replacement together with a low dosage of GH (mimicking a male G H secretion pattern), except for androsterone glucuronidation activity where both GH and cortisol/thyroxine treatments reinforced the decrea sing effect of hypophysectomy. Variations in protein amounts were corr elated to variations in bilirubin, testosterone and androsterone conju gation activities induced by hypo physectomy and GH treatment. Reverse transcription-polymerase chain reaction (RT-PCR) mRNA analysis of bil irubin cluster isoforms or uridine diphosphate glucuronosyltransferase 1B1 (UGT1B1), UGT1B2 and UGT1B5 showed that GH controlled the differe nt isoforms involved in bilirubin glucuronidation differentially at a pretranslational level. BIOCHEM PHARMACOL 53;11:1631-1647, 1997. (C) 1 997 Elsevier Science Inc.