Arzneimittelforschung 2011; 61(2): 98-103
DOI: 10.1055/s-0031-1296174
Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs
Editio Cantor Verlag Aulendorf (Germany)

Disappearance of sexual dimorphism in triptolide metabolism in monosodium glutamate treated neonatal rats

Li Liu
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
2   Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou, P.R. China
,
Zhenzhou Jiang
3   Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing, P. R. China
,
Xiaofeng Huang
4   Department of Geratology, Changzhou De An Hospital, Chang Zhou, P. R. China
,
Jing Liu
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Juan Zhang
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Jingwei Xiao
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Qingli Bao
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Jing Wen
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Shuang Zhang
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Dan Zhu
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Pinghu Zhang
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
,
Luyong Zhang
1   Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
› Author Affiliations
Further Information

Publication History

Publication Date:
28 November 2011 (online)

Abstract

Triptolide (CAS 38748-32-2), a major active component of Tripterygium wilfordii Hook F (TWHF), was reported to be sex-dependently metabolized mainly due to sex-related expression of CYP3A2. Sexual dimorphism in the expression of CYP isoforms is affected by sex difference in daily rhythm of growth hormone (GH) secretion. Neonatal administration of monosodium glutamate (MSG) can produce latent developmental defects in GH secretion and associated sex-dependent hepatic enzymes. In the present study, the triptolide metabolism, CYP3A2 expression and CYP3A-dependent activity were evaluated in Sprague-Dawley rats treated neonatally with MSG (4 mg/g) or saline (control) on postnatal days 1, 3, 5, 7 and 9. Treatment with MSG during the neonatal period in both sexes caused a number of disorders characterized by stunted body growth, notable obesity and suppression of GH secretion to barely detectable levels. In addition, neonatal treatment with MSG nearly eliminated the male-specific CYP3A2 expression and significantly reduced the microsomal erythromycin N-demethylation activity in males, while having no effects on CYP3A2 protein in females. Consistent with the P450 findings, the sexual dimorphism of triptolide metabolism completely disappeared in MSG-treated rats. This suggested that neonatal MSG treatment could eliminate the sex-dependent difference in metabolism of triptolide by suppressing CYP3A2 expression and activity in males to the same extent as females.

 
  • References

  • 1 Chen BJ. Triptolide, a novel immunosuppressive and antiinflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F. Leuk Lymphoma. 2001; 42 (3) 253-65
  • 2 Huynh PN, Hikim AP, Wang C, Stefonovic K, Lue YH, Leung A et al Long-term effects of triptolide on spermatogenesis, epididymal sperm function, and fertility in male rats. J Androl. 2000; 21 (5) 689-99
  • 3 Panichakul T, Intachote P, Wongkajorsilp A, Sripa B, Sirisinha S. Triptolide sensitizes resistant cholangiocarcinoma cells to TRAIL-induced apoptosis. Anticancer Res. 2006; 26 (1A) 259-65
  • 4 Yang S, Chen J, Guo Z, Xu XM, Wang L, Pei XF et al Triptolide inhibits the growth and metastasis of solid tumors. Mol Cancer Ther. 2003; 2 (1) 65-72
  • 5 Lipsky PE, Tao XL. A potential new treatment for rheumatoid arthritis: thunder god vine. Semin Arthritis Rheum. 1997; 26 (5) 713-23
  • 6 Liu MX, Dong J, Yang YJ, Yang XL, Xu HB [Progress in research on triptolide] Zhongguo Zhong Yao Za Zhi. 2005; 30 (3) 170-4
  • 7 Li W, Liu Y, He YQ, Zhang JW, Gao Y, Ge GB et al Characterization of triptolide hydroxylation by cytochrome P450 in human and rat liver microsomes. Xenobiotica. 2008; 38 (12) 1551-65
  • 8 Ye X, Li W, Yan Y, Mao C, Cai R, Xu H et al Effects of cytochrome P4503A inducer dexamethasone on the metabolism and toxicity of triptolide in rat. Toxicol Lett. 2010; 192 (2) 212-20
  • 9 Liu L, Jiang Z, Liu J, Huang X, Wang T, Zhang Y et al Sex differences in subacute toxicity and hepatic microsomal metabolism of triptolide in rats. Toxicology. 2010; 271 (1-2) 57-63
  • 10 Waxman DJ, Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol. 2009; 76 (2) 215-28
  • 11 Kaneko K, Uchida K, Kobayashi T, Miura K, Tanokura K, Hoshino K et al Sex-dependent toxicity of a novel acyl-CoA:holesterol acyltransferase inhibitor, YIC-C8-434, in relation to sex-specific forms of cytochrome P450 in rats. Toxicol Sci. 2001; 64 (2) 259-68
  • 12 Waxman DJ, O'Connor C. Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol. 2006; 20 (11) 2613-29
  • 13 Tannenbaum GS, Martin JB. Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat. Endocrinology. 1976; 98 (3) 562-70
  • 14 Shapiro BH, Agrawal AK, Pampori NA. Gender differences in drug metabolism regulated by growth hormone. Int J Biochem Cell Biol. 1995; 27 (1) 9-20
  • 15 Waxman DJ. Growth hormone pulse-activated STAT5 signalling: a unique regulatory mechanism governing sexual dimorphism of liver gene expression. Novartis Found Symp. 2000; 227: 61-74 discussion 5-81.
  • 16 Pampori NA, Agrawal AK, Waxman DJ, Shapiro BH. Differential effects of neonatally administered glutamate on the ultradian pattern of circulating growth hormone regulating expression of sex-dependent forms of cytochrome P450. Biochem Pharmacol. 1991; 41 (9) 1299-309
  • 17 Pampori NA, Shapiro BH. Effects of neonatally administered monosodium glutamate on the sexually dimorphic profiles of circulating growth hormone regulating murine hepatic monooxygenases. Biochem Pharmacol. 1994; 47 (7) 1221-9
  • 18 Nash T. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J. 1953; 55 (3) 416-21
  • 19 Wang RW, Newton DJ, Scheri TD, Lu AY. Human cytochrome P450 3A4-catalyzed testosterone 6 betahydroxylation and erythromycin N-demethylation. Competition during catalysis. Drug Metab Dispos. 1997; 25 (4) 502-7
  • 20 Kaufhold A, Nigam PK, Dhir RN, Shapiro BH. Prevention of latently expressed CYP2C11, CYP3A2, and growth hormone defects in neonatally monosodium glutamatetreated male rats by the N-methyl-D-aspartate receptor antagonist dizocilpine maleate. J Pharmacol Exp Ther. 2002; 302 (2) 490-6
  • 21 Corder R, Saudan P, Mazlan M, McLean C, Gaillard RC. Depletion of hypothalamic growth hormone-releasing hormone by neonatal monosodium glutamate treatment reveals an inhibitory effect of betamethasone on growth hormone secretion in adult rats. Neuroendocrinology. 1990; 51 (1) 85-92
  • 22 Agrawal AK, Shapiro BH. Gender, age and dose effects of neonatally administered aspartate on the sexually dimorphic plasma growth hormone profiles regulating expression of the rat sex-dependent hepatic CYP isoforms. Drug Metab Dispos. 1997; 25 (11) 1249-56
  • 23 Jarukamjorn K, Sakuma T, Jaruchotikamol A, Ishino Y, Oguro M, Nemoto N. Modified expression of cytochrome P450 mRNAs by growth hormone in mouse liver. Toxicology. 2006; 219 (1-3) 97-105
  • 24 Legraverend C, Mode A, Wells T, Robinson I, Gustafsson JA. Hepatic steroid hydroxylating enzymes are controlled by the sexually dimorphic pattern of growth hormone secretion in normal and dwarf rats. FASEBJ. 1992; 6 (2) 711-8
  • 25 Pampori NA, Shapiro BH. Feminization of hepatic cytochrome P450s by nominal levels of growth hormone in the feminine plasma profile. Mol Pharmacol. 1996; 50 (5) 1148-56
  • 26 Pampori NA, Shapiro BH. Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile. Endocrinology. 1999; 140 (3) 1245-54
  • 27 Kawai M, Bandiera SM, Chang TK, Bellward GD. Growth hormone regulation and developmental expression of rat hepatic CYP3A18, CYP3A9, and CYP3A2. Biochem Pharmacol. 2000; 59 (10) 1277-87
  • 28 Shapiro BH, Albucher RC, MacLeod JN, Bitar MS. Normal levels of hepatic drug-metabolizing enzymes in neonatally induced, growth hormone-deficient adult male and female rats. DrugMetab Dispos. 1986; 14 (5) 585-9
  • 29 Gustafsson JA, Eneroth P, Pousette A, Skett P, Sonnenschein C, Stenberg A et al Programming and differentiation of rat liver enzymes. J Steroid Biochem. 1977; 8 (5) 429-43
  • 30 Jansson JO, Ekberg S, Isaksson OG, Eden S. Influence of gonadal steroids on age- and sex-related secretory patterns of growth hormone in the rat. Endocrinology. 1984; 114 (4) 1287-94
  • 31 Kennedy M. Hormonal regulation of hepatic drug-metabolizing enzyme activity during adolescence. Clin Pharmacol Ther. 2008; 84 (6) 662-73