Effects of testosterone and growth hormone treatment on hepatic microsomal P450 expression in the diabetic rat

KE Thummel and JB Schenkman

University of Connecticut Health Center, Farmington 06032.

The profile of hepatic microsomal cytochrome P450 expressed in the male and female rat was dramatically altered by streptozotocin-induced diabetes. In the diabetic male, P450 forms IIC11, IIC13, IIA2, and IIIA2 were suppressed and forms IIA1 and IIC12 were induced to the levels observed in the immature male rat. A 6- to 8-fold induction of P450 IIE1 was detected in both male and female diabetic rats. A member of the P450 IIIA family was also induced in the diabetic female rat. Accompanying the change in P450 profile in the diabetic male rat was reduction in circulating testosterone and tetraiodothyronine concentrations and a sharp diminution of the normally pulsatile pattern of growth hormone secretion. In contrast to the male rat, the growth hormone secretion pattern in the diabetic female rat was unchanged from control. The hormone and P450 profiles detected in the diabetic male rat suggest a reversion to an immature physiological state. Testosterone replacement treatments carried out for 2 weeks slightly but significantly affected the suppression of P450 IIC11 and reversed the changes in P450 IIA2, IIIA2, and IIC12 in the diabetic male, without altering the suppressed state of growth hormone secretion. However, 1 week of human growth hormone, administered intravenously every 4 hr to diabetic male rats, failed to significantly reverse the diabetes-induced changes in hepatic cytochromes P450, in particular forms IIC11 and IIE1, despite the presence of an episodic plasma hGH profile. An induction of P450 IIE1 in diabetic female rats, without a reduction in growth hormone secretion, suggests that its induction in diabetes in both sexes is not related to changes in growth hormone. In addition, the results of testosterone treatment on the expression of IIC12, IIA2, and IIIA2 in the diabetic male rat suggest a regulatory role for this hormone that does not involve the pituitary secretion of growth hormone. However, the lack of effect of human growth hormone treatment in the diabetic male on levels of individual P450 forms indicates that in diabetes there may be a change in the ability of the male rat hepatocyte to respond to a somatic signal, possibly as a result of the changes in other hormone factors.

Volume 37, Issue 1, pp. 119-129, 01/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				Y. C. Kim, J. H. Lee, S. H. Kim, and M. G. Lee Effect of CYP3A1(23) Induction on Clarithromycin Pharmacokinetics in Rats with Diabetes Mellitus Antimicrob. Agents Chemother., June 1, 2005; 49(6): 2528 - 2532. [Abstract] [Full Text] [PDF]

				Y. H. Suh, Y. Kim, J. H. Bang, K. S. Choi, J. W. Lee, W.-H. Kim, T. J. Oh, S. An, and M. H. Jung Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats J. Mol. Endocrinol., April 1, 2005; 34(2): 299 - 315. [Abstract] [Full Text] [PDF]

				J. Ma, J. Graves, J. A. Bradbury, Y. Zhao, D. L. Swope, L. King, W. Qu, J. Clark, P. Myers, V. Walker, et al. Regulation of Mouse Renal CYP2J5 Expression by Sex Hormones Mol. Pharmacol., March 1, 2004; 65(3): 730 - 743. [Abstract] [Full Text] [PDF]

				A. Moncion, N. T. Truong, A. Garrone, P. Beaune, R. Barouki, and I. de Waziers Identification of a 16-Nucleotide Sequence That Mediates Post-transcriptional Regulation of Rat CYP2E1 by Insulin J. Biol. Chem., November 22, 2002; 277(48): 45904 - 45910. [Abstract] [Full Text] [PDF]

				G. J. Pass, W. Becker, R. Kluge, K. Linnartz, L. Plum, K. Giesen, and H.-G. Joost Effect of Hyperinsulinemia and Type 2 Diabetes-Like Hyperglycemia on Expression of Hepatic Cytochrome P450 and Glutathione S-Transferase Isoforms in a New Zealand Obese-Derived Mouse Backcross Population J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 442 - 450. [Abstract] [Full Text] [PDF]

				A. M. Watson, S. M. Poloyac, G. Howard, and R. A. Blouin Effect of Leptin on Cytochrome P-450, Conjugation, and Antioxidant Enzymes in the ob/ob Mouse Drug Metab. Dispos., June 1, 1999; 27(6): 695 - 700. [Abstract] [Full Text]

				K. J. Woodcroft and R. F. Novak Insulin Differentially Affects Xenobiotic-Enhanced, Cytochrome P-450 (CYP)2E1, CYP2B, CYP3A, and CYP4A Expression in Primary Cultured Rat Hepatocytes J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 1121 - 1127. [Abstract] [Full Text]

				D. L. Kroetz, P. Yook, P. Costet, P. Bianchi, and T. Pineau Peroxisome Proliferator-activated Receptor alpha  Controls the Hepatic CYP4A Induction Adaptive Response to Starvation and Diabetes J. Biol. Chem., November 20, 1998; 273(47): 31581 - 31589. [Abstract] [Full Text] [PDF]

				M. D. Anderson, S. M. Bandiera, T. K. H. Chang, and G. D. Bellward Effect of Androgen Administration During Puberty on Hepatic CYP2C11, CYP3A, and CYP2A1 Expression in Adult Female Rats Drug Metab. Dispos., October 1, 1998; 26(10): 1031 - 1038. [Abstract] [Full Text]

				H.-M. Peng and M. J. Coon Regulation of Rabbit Cytochrome P450 2E1 Expression in HepG2 Cells by Insulin and Thyroid Hormone Mol. Pharmacol., October 1, 1998; 54(4): 740 - 747. [Abstract] [Full Text]

				W. Qu, R. A. Rippe, J. Ma, P. Scarborough, C. Biagini, F. T. Fiedorek, G. S. Travlos, C. Parker, and D. C. Zeldin Nutritional Status Modulates Rat Liver Cytochrome P450 Arachidonic Acid Metabolism Mol. Pharmacol., September 1, 1998; 54(3): 504 - 513. [Abstract] [Full Text]