Abstract
Aim:
Fetal adrenal, which synthesizes steroid hormones, is critical to fetal growth and development. Our recent research showed that some xenobiotics could interfere with steroidogenesis and induce intrauterine growth retardation in rats. The study on the characteristics of biotransformation enzymes in fetal adrenals still seems to be important with respect to possible significance in xenobiotic-induced fetal development toxicity. In this study, the activities of several important xenobiotic-related phase I and phase II enzymes in human fetal adrenals were examined and compared with those in fetal livers.
Methods:
The activity and mRNA expression were determined by enzymatic analysis and RT-PCR.
Results:
The levels of cytochrome (CYP)2A6, CYP2E1, and CYP3A7 isozymes in fetal adrenals were 82%, 92%, and 33% of those in fetal livers, respectively. There was a good positive correlation between adrenal CYP2A6 activity and gestational time. The values of α glutathione S-transferase (GST), φGST, and μGST in adrenals were 0.5, 4.4, and 8.3-fold of those in the livers, respectively, and the activity of adrenal πGST was negatively correlated with gestational time. The uridine diphosphoglucuronyl transferase activities, which were measured using p-hydroxy-biphenyl and 7-hydroxy-4-methylcoumarin as substrates, were 9% and 3%, respectively, of those in the fetal livers.
Conclusion:
Our investigation suggested that adrenal could be an important xenobiotic-metabolizing organ in fetal development and may play a potential role in xenobiotic-induced fetal development toxicity.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Syme MR, Paxton JW, Keelan JA . Drug transfer and metabolism by the human placenta. Clin Pharmacokinet 2004; 43: 487–514.
Blake MJ, Castro L, Leeder JS, Kearns GL . Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med 2005; 10: 123–38.
Tsuchiya Y, Nakajima M, Yokoi T . Cytochrome CYP-mediated metabolism of estrogens and its regulation in human. Cancer Lett 2005; 227: 115–24.
Choudhary D, Jansson I, Sarfarazi M, Schenkman JB . Xenobiotic-metabolizing cytochromes CYP in ontogeny: evolving perspective. Drug Metab Rev 2004; 36: 549–68.
Philpot RM . Characterization of cytochrome CYP in extrahepatic tissues. Methods Enzymol 1991; 206: 623–31.
Coon MJ . Cytochrome CYP: nature's most versatile biological catalyst. Annu Rev Pharmacol Toxicol 2005; 45: 1–25.
Briggs GG . Drug effects on the fetus and breast-fed infant. Clin Obstet Gynecol 2002; 45: 6–21.
Rainey WE, Rehman KS, Carr BR . The human fetal adrenal: making adrenal androgens for placental estrogens. Semin Reprod Med 2004; 22: 327–36.
Langlois D, Li JY, Saez JM . Development and function of the human fetal adrenal cortex. J Pediatr Endocrinol Metab 2002; 5: 1311–22.
Albrecht ED, Henson MC, Walker ML, Pepe GJ . Modulation of adrenocorticotropin-treated baboon fetal adrenal dehydroepiandrosterone formation in vitro by estrogen at mid- and late gestation. Endocrinology 1990; 126: 3083–8.
Sarasin A, Schlumpf M, Muller M . Adrenal-mediated rather than direct effects of nicotine as a basis of altered sex steroid synthesis in fetal and neonatal rat. Reprod Toxicol 2003; 17: 153–62.
Wang H, Huang M, Peng RX, Je J . Influences of 3-methylcholanthrene, phenobarbital and dexamethasone on xenobiotic metabolizing-related cytochrome P450 enzymes and steroidogenesis in human fetal adrenal cortical cells. Acta Pharmacol Sin 2006; 27: 1093–6.
Chen M, Wang T, Liao ZX, Pan XL, Feng YH, Wang H . Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat. Exp Toxicol Pathol. 2007 Sep 17; [Epub ahead of print].
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ . Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265–75.
Burke MD, Prough RA, Mayer RT . Characteristics of a microsomal cytochrome P-448-mediated reaction. Ethoxyresorufin O-deethylation. Drug Metab Dispos 1977; 5: 1–8.
Denton TT, Zhang X, Cashman JR . Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6. Biochem Pharmacol 2004; 67: 751–6.
Peng RX, Lei SB, Gao P . The capacity of drug metabolism in Chinese fetal livers: metabolism of ethylomorphine, aminopyrine and aniline. Asian Pac J Pharmarcol 1990; 5: 13–8.
Sanwald P, Blankson EA, Dulery BD, Schoun J, Huebert ND, Dow J . Isocratic high-performance liquid chromatographic method for the separation of testosterone metabolites. J Chromatogr B 1995; 672: 207–15.
Li Y . Study on phase II enzymes of drug metabolism. In: Zhang JT, editor Modern methods of pharmacological experiment. Peking: The Union Press of Peking Medical University and Chinese Academy of Medical Sciences; 1997. p 1656–7 (in Chinese).
Ouwerkerk-Mahadevan S, Mulder GJ . Inhibition of glutathione conjugation in the rat in vivo by analogues of glutathione conjugates. Chem Biol Interact 1998; 111–112: 163–76.
Van Iersel ML, van Lipzig MM, Rietjens IM, Vervoort J, van Bladeren PJ . GSTP1-1 stereospecifically catalyzes glutathione conjugation of ethacrynic acid. FEBS Lett 1998; 441: 153–7.
Hakkola J, Pasanen M, Purkunen R, Saarikoski S, Pelkonen O, Maenpaa J, et al. Expression of xenobiotic-metabolizing cytochrome CYP forms in human adult and fetal liver. Biochem Pharmacol 1994; 48: 59–64.
Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T . Expression of CYP3A in the human liver—evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 1997; 247: 625–34.
Young AM, Allen CE, Audus KL . Efflux transporters of the human placenta. Adv Drug Deliv Rev. 2003; 55: 125–32.
Yan YE, Wang H, Feng YH . Alterations of placental cytochrome P450 1A1 and P-glycoprotein in tobacco-induced intrauterine growth retardation in rats. Acta Pharmacol Sin 2005; 26: 1387–94.
Yan GL . Fetal endocrinology. Peking: People's Medical Publishing House; 1983. p 24 (in Chinese).
Shimada T, Fujii-Kuriyama Y . Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes CYP 1A1 and 1B1. Cancer Sci 2004; 95: 1–6.
Omiecinski CJ, Redlich CA, Costa P . Induction and developmental expression of cytochrome CYP1A1 messager RNA in rat and human tissues: detection by the polymerase chain reaction. Cancer Res 1990; 50: 4315–21.
Gu J, Su T, Chen Y, Zhang QY, Ding X . Expression of biotransformation enzymes in human fetal olfactory mucosa: potential roles in developmental toxicity. Toxicol Appl Pharmacol 2000; 165: 158–61.
Roberts BJ, Shoaf SE, Jeong KS, Song BJ . Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal: evidence that CYP2E1 possesses a rapid phase half-life of 6 hours or less. Biochem Biophys Res Commun 1994; 205: 1064–71.
Wilkening S, Bader A . Differential regulation of CYP3A4 and CYP3A7 by dimethylsulfoxide in primary human hepatocytes. Basic Clin Pharmacol Toxicol 2004; 95: 92–3.
Ring JA, Ghabrial H, Ching MS, Smallwood RA, Morgan DJ . Fetal hepatic drug elimination. Pharmacol Ther 1999; 84: 429–45.
Hume R, Coughtrie MW, Burchell B . Differential localisation of UDP-glucuronosyltransferase in kidney during human embryonic and fetal development. Arch Toxicol 1995; 69: 242–7.
Chauhan D P, Miller MS, Owens IS, Anderson LM . Gene expression, ontogeny and transplacental induction of hepatic UDP-glucuronosyl transferase activity in mice. Dev Pharmacol Ther 1991; 16: 139–49.
Sharma R, Yang Y, Sharma A, Awasthi S, Awasthi YC . Antioxidant role of glutathione S-transferases: protection against oxidant toxicity and regulation of stress-mediated apoptosis. Antioxid Redox Signal 2004; 6: 289–300.
Mera N, Ohmori S, Itahashi K, Kiuchi M, Igarashi T, Rikihisa T, et al. Immunochemical evidence for the occurrence of Mu class glutathione S-transferase in human fetal livers. J Biochem 1994; 116: 315–20.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the National Natural Science Foundation of China (No 30672566).
Rights and permissions
About this article
Cite this article
Wang, H., Ping, J., Peng, Rx. et al. Changes of multiple biotransformation phase I and phase II enzyme activities in human fetal adrenals during fetal development. Acta Pharmacol Sin 29, 231–238 (2008). https://doi.org/10.1111/j.1745-7254.2008.00738.x
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1111/j.1745-7254.2008.00738.x
Keywords
This article is cited by
-
Development and evaluation of a three-component micro-cutting force wireless measurement apparatus and method in turning-milling compound machining
The International Journal of Advanced Manufacturing Technology (2017)
-
Development and evaluation of a 3-component lapping force measurement apparatus in micro component manufacturing
The International Journal of Advanced Manufacturing Technology (2015)
