Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Hormonal Regulation of Cytochrome P450 in Rat Liver

  • Chapter
Cytochrome P450

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 105))

Abstract

A number of lipophilic xenobiotics and endobiotics are biotransformed oxidatively by cytochrome P450 in mammalian livers. Many different forms of cytochrome P450 are contained in this organ and each shows a broad substrate specificity. Thus, cytochrome P450 has been considered as a family of polysubstrate enzymes, and we now know that cytochrome P450 constitutes a supergene family through the characterization of the purified proteins and cDNAs. These studies also provide information on the diversity in the regulatory mechanism of hepatic cytochromes P450: Some of these forms are expressed in age- and/or sex-related manners in livers of experimental animals, especially in rats (Kato 1974; Kato and Kamataki 1982). These differences are governed by sex steroids and other hormones. Changes in drug-metabolizing activities observed in physiological and pathological conditions are now recognized to be associated with an alteration in endocrine factors. In this section, the current understanding on the regulation and expression of sex-related cytochrome P450 forms in rat liver is reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 74.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Ahir S, Mohla S (1989) Regulation of renal N-nitrosodimethylamine demethylase activity by androgens, progestin, glucocorticoid, and estrogen in BALB/c mice. Cancer Res 49: 3737–3741

    PubMed  CAS  Google Scholar 

  • Arlotto M, Parkinson A (1989) Identification of cytochrome P-450a (P-450IIA1) as the principal testosterone 7a-hydroxylase in rat liver microsomes and its regulation by thyroid hormones. Arch Biochem Biophys 270: 458–471

    Article  PubMed  CAS  Google Scholar 

  • Bandiera S, Ryan DE, Levin W, Thomas PE (1986) Age- and sex-related expression of cytochrome P450f and P450g in rat liver. Arch Biochem Biophys 248: 658–676

    Article  PubMed  CAS  Google Scholar 

  • Bellward GD, Chang T, Rodrigues B, McNeill JH, Maines S, Ryan DE, Levin W, Thomas PE (1988) Hepatic cytochrome P-450j induction in the spontaneously diabetic BB rat. Mol Pharmacol 33: 140–143

    PubMed  CAS  Google Scholar 

  • Colby HD (1980) Regulation of hepatic drug and steroid metabolism by androgens and estrogens. In: Thomas JA, Singhal RL (ed) Advances in sex hormone research. Urban and Schwarzenberg, Miinchen, pp 27–71

    Google Scholar 

  • Degawa M, Miura S, Hashimoto Y (1990) Androgen-dependent renal microsomal cytochrome P-450 responsible for N-hydroxylation and mutagenic activation of 3-methoxy-4-aminoazobenzene in the BALB/c mouse. Cancer Res 50: 2729–2733

    PubMed  CAS  Google Scholar 

  • Donahue BS, Skottnerlundin A, Morgan ET (1991) Growth hormone-dependent and -independent regulation of cytochrome P-450 isozyme expression in streptozotocin-diabetic rats. Endocrinology 128: 2065–2076

    Article  PubMed  CAS  Google Scholar 

  • Dong Z, Hong J, Ma Q, Li D, Bullock J, Gonzalez FJ, Park SS, Gelboin HV, Yang CS (1988) Mechanism of induction of cytochrome P-450ac (p-450j) in chemically induced and spontaneously diabetic rats. Arch Biochem Biophys 263: 29–35

    Article  PubMed  CAS  Google Scholar 

  • Edén S (1979) Age- and sex-related differences in episodic growth hormone secretion in the rat. Endocrinology 105: 555–560

    Article  PubMed  Google Scholar 

  • Favreau LV, Schenkman JB (1988) Composition changes in hepatic microsomal cytochrome P-450 during onset of streptozocin-induced diabetes and during insulin treatment. Diabetes 37: 577–584

    Article  PubMed  CAS  Google Scholar 

  • Favreau LV, Malchoff DM, Mole JE, Schenkman JB (1987) Responses to insulin by two forms of rat hepatic microsomal cytochrome P-450 that undergo major (RLM6) and minor (RLM5b) elevations in diabetes. J Biol Chem 262: 14319–14326

    PubMed  CAS  Google Scholar 

  • Funae Y, Imaoka S, Shimojo N (1988) Purification and characterization of diabetes-inducible cytochrome P-450. Biochem Int 16: 503–509

    PubMed  CAS  Google Scholar 

  • Gustafsson J-A, Mode A, Norstedt G, Skett P (1983) Sex steroid induced changes in hepatic enzymes. Annu Rev Physiol 45: 51–60

    Article  PubMed  CAS  Google Scholar 

  • Harada N, Negishi M (1984) Mouse liver testosterone 15a-hydroxylase (cytochrome P-45015a) Purification, regioselectivity, stereospecificity, and sex-dependent expression. J Biol Chem 259: 1265–1271

    PubMed  CAS  Google Scholar 

  • Hong J-Y, Ning DS, Ma B-L, Lee M-J, Pan J, Yang CS (1990) Roles of pituitary hormones in the regulation of hepatic cytochrome P450IIE1 in rats and mice. Arch Biochem Biophys 281: 132–138

    Article  PubMed  CAS  Google Scholar 

  • Janeczko R, Waxman DJ, Leblanc GA, Morville A, Adesnik M (1990) Hormonal regulation of levels of the messenger RNA encoding hepatic P450 2C (IIC11), a constitutive male-specific form of cytochrome P450. Mol Endocrinol 4: 295–303

    Article  PubMed  CAS  Google Scholar 

  • Jansson I, Mole J, Schenkman JB (1985) Purification and characterization of a new form (RLM2) of liver microsomal cytochrome P-450 from untreated rat. J Biol Chem 260: 7084–7093

    PubMed  CAS  Google Scholar 

  • Kamataki T, Maeda K, Yamazoe Y, Nagai T, Kato R (1981) Partial purification and characterization of cytochrome P-450 responsible for the occurrence of sex difference in drug metabolism in the rat. Biochem Biophys Res Commun 103: 1–7

    Article  PubMed  CAS  Google Scholar 

  • Kamataki T, Maeda K, Yamazoe Y, Nagai T, Kato R (1983) Sex difference of cytochrome P-450 in the rat: purification, characterization, and quantitation of constitutive forms of cytochrome P-450 from liver microsomes of male and female rats. Arch Biochem Biophys 225: 758–770

    Article  PubMed  CAS  Google Scholar 

  • Kamataki T, Maeda K, Shimada M, Nagai T, Kato R (1984) Neonatal testosterone imprinting of hepatic microsomal drug metabolism and a male-specific form of cytochrome P-450 in the rat. J Biochem (Tokyo) 96: 1939–1942

    CAS  Google Scholar 

  • Kamataki T, Maeda K, Shimada M, Kitani K, Nagai T, Kato R (1985a) Age-related alteration in the activities of drug-metabolizing enzymes and contents of sex-specific forms of cytochrome P-450 in liver microsomes from male and female rats. J Pharmacol Exp Ther 233: 222–228

    PubMed  CAS  Google Scholar 

  • Kamataki T, Shimada M, Maeda K, Kato R (1985b) Pituitary regulation of sex-specific forms of cytochrome P-450 in liver microsomes of rats. Biochem Biophys Res Commun 130: 1247–1253

    Article  PubMed  CAS  Google Scholar 

  • Kato R (1974) Sex-related differences in drug metabolism. Drug Metab Rev 3: 1–32

    Article  PubMed  CAS  Google Scholar 

  • Kato R, Gillette JR (1965) Sex differences in the effects of abnormal physiological states on the metabolism of drugs by rat liver microsomes. J Pharmacol Exp Ther 150: 285–291

    PubMed  CAS  Google Scholar 

  • Kato R, Kamataki T (1982) Cytochrome P-450 as a determinant of sex difference of drug metabolism in the rat. Xenobiotica 12: 787–800

    Article  PubMed  CAS  Google Scholar 

  • Kato R, Kamataki T (1985) Mechanism of induction of sex specific forms of cytochrome P-450 in liver microsomes of rats. In: Verexzkey L, Magyar K (ed) Cytochrome P-450, biochemistry, biophysics and induction. Akademiai Kiado, Budapest, pp 219–226

    Google Scholar 

  • Kato R, Takahashi A (1968) Thyroid hormone and activities of drug-metabolizing enzymes and electron transport systems of rat liver microsomes. Mol Pharmacol 4: 109–120

    PubMed  CAS  Google Scholar 

  • Kato R, Yamazoe Y, Shimada M, Murayama N, Kamataki T (1986) Effect of growth hormone and ectopic transplantation of pituitary gland on sex-specific forms of cytochrome P-450 and testosterone and drug oxidations in rat liver. J Biochem (Tokyo) 100: 895–902

    CAS  Google Scholar 

  • MacGeoch C, Morgan ET, Gustafsson J-A (1985) Hypothalamo-pituitary regulation of cytochrome P-45015g apoprotein levels in rat liver. Endocrinology 117: 2085–2092

    Article  PubMed  CAS  Google Scholar 

  • Maeda K, Kamataki T, Nagai T, Kato R (1984) Postnatal development of constitutive forms of cytochrome P-450 in liver microsomes of male and female rats. Biochem Pharmacol 33: 509–512

    Article  PubMed  CAS  Google Scholar 

  • McClellan-Green PD, Linko P, Yeowell HN, Goldstein JA (1989) Hormonal regulation of male-specific rat cytochrome P-450g (P-450IIC13) by androgens and the pituitary. J Biol Chem 264: 18960–18965

    PubMed  CAS  Google Scholar 

  • Mode A, Wiersma-Larsson E, Gustafsson J-A (1989a) Transcriptional and posttranscriptional regulation of sexually differentiated rat liver cytochrome P-450 by growth hormone. Mol Endocrinol 89: 1142–1147

    Article  Google Scholar 

  • Mode A, Wiersma-Larsson E, Strom A, Zaphiropoulos PG, Gustafsson J-A (1989b) A dual role of growth hormone as a feminizing and masculinizing factor in the control of sex-specific cytochrome P-450 isozymes in rat liver. J Endocrinol 120: 311–317

    Article  PubMed  CAS  Google Scholar 

  • Morgan ET, MacGeoch C, Gustafsson J-A (1985) Hormonal and developmental regulation of expression of the hepatic microsomal steroid 16a-hydroxylase cytochrome P-450 apoprotein in the rat. J Biol Chem 260: 11895–11898

    PubMed  CAS  Google Scholar 

  • Murayama N, Shimada M, Yamazoe Y, Kato R (1991) Difference in the susceptibility of two phenobarbital-inducible forms, P450IIB1 and P450IIB2, to thyroid hormone-induced and growth hormone-induced suppression in rat liver: phenobarbital-inducible P450IIB2 suppression by thyroid hormone acting directly, but not through the pituitary system. Mol Pharmacol 39: 811–817

    PubMed  CAS  Google Scholar 

  • Nagata K, Gonzalez FJ, Yamazoe Y, Kato R (1990) Purification and characterization of four catalytically active testosterone 6(3-hydroxylase P-450s from rat liver microsomes: comparison of a novel form with three structurally and functionally related forms. J Biochem (Tokyo) 107: 718–725

    CAS  Google Scholar 

  • Nagata K, Shimada M, Yamazoe Y, Kato R (1991) Regulations of male dominant P-450Md mRNA in rat liver by hormonal factors and xenobiotics. Jpn J Pharmacol 57: 123–126

    Article  PubMed  CAS  Google Scholar 

  • Ram PA, Waxman DJ (1991) Hepatic P450 expression in hypothyroid rats: differential responsiveness of male-specific P450 form 2a (IIIA2), 2c (IIC11), and RLM2 (IIA2) to thyroid hormone. Mol Endocrinol 5: 13–20

    Article  PubMed  CAS  Google Scholar 

  • Sasamura H, Nagata K, Yamazoe Y, Shimada M, Saruta T, Kato R (1990) Effect of growth hormone on rat hepatic cytochrome P-450f mRNA: a new mode of regulation. Mol Cell Endocrinol 68: 53–60

    Article  PubMed  CAS  Google Scholar 

  • Shimada M, Murayama N, Yamazoe Y, Kamataki T, Kato R (1987) Further studies on the persistence of neonatal androgen imprinting on sex-specific cytochrome P-450, testosterone and drug oxidations. Jpn J Pharmacol 45: 467–478

    Article  PubMed  CAS  Google Scholar 

  • Shimada M, Nagata K, Murayama N, Yamazoe Y, Kato R (1989) Role of growth hormone in modulating the constitutive and phenobarbital-induced levels of two P-4506p (testosterone 6(3-hydroxylase) mRNAs in rat livers. J Biochem (Tokyo) 106: 1030–1034

    CAS  Google Scholar 

  • Song B-J, Matsunaga T, Hardwick JP, Park SS, Veech RL, Yang CS, Gelboin HV, Gonzalez FJ (1987) Stabilization of cytochrome P450j messenger ribonucleic acid in the diabetic rat. Mol Endocrinol 1: 542–547

    Article  PubMed  CAS  Google Scholar 

  • Squires EJ, Negishi M (1990) Tissue-specific regulation of cytochrome P-450 dependent testosterone 15a-hydroxylase. Can J Physiol Pharmacol 68: 769–776

    Article  PubMed  CAS  Google Scholar 

  • Thummel KE, Schenkman JB (1990) Effects of testosterone and growth hormone treatment on hepatic microsomal P450 expression in the diabetic rat. Mol Pharmacol 37: 119–129

    PubMed  CAS  Google Scholar 

  • Waxman DJ, Dannan GA, Guengerich FP (1985) Regulation of rat hepatic cytochrome P-450: age-dependent expression, hormonal imprinting and xenobiotic inducibility of sex-specific isoenzymes. Biochemistry 24: 4409–4417

    Article  PubMed  CAS  Google Scholar 

  • Waxman DJ, Morrissey JJ, Leblanc GA (1989) Female-predominant rat hepatic P-450 forms j (IIE1) and 3 (IIA1) are under hormonal regulatory controls distinct from those of the sex-specific P-450 forms. Endocrinology 124: 2954–2966

    Article  PubMed  CAS  Google Scholar 

  • Waxman DJ, Ram PA, Notani G, Leblanc GA, Alberta JA, Morrissey JJ, Sundseth SS (1990) Pituitary regulation of the male-specific steroid 6[3-hydroxylase P-450 2a (gene product IIIA2) in adult rat liver. Suppressive influence of growth hormone and thyroxine acting at a pretranslational level. Mol Endocrinol 4: 447–454

    Article  PubMed  CAS  Google Scholar 

  • Westin S, Strom A, Gustafsson J-A, Zaphiropoulos PG (1990) Growth hormone regulation of the cytochrome P-450IIC subfamily in the rat: inductive, repressive, and transcriptional effects on P-450f (IIC7) and P-450PBI (IIC6) gene expression. Mol Pharmacol 38: 192–197

    PubMed  CAS  Google Scholar 

  • Wilson JT (1968) The effect of a pituitary mammotropic tumor on hepatic microsomal drug metabolism in the rat. Biochem Pharmacol 17: 1449–1457

    Article  PubMed  CAS  Google Scholar 

  • Yamazoe Y, Shimada M, Kamataki T, Kato R (1986a) Effect of hypophysectomy and growth hormone treatment on sex-specific forms of cytochrome P-450 in relation to drug and steroid metabolisms in rat liver microsomes. Jpn J Pharmacol 42: 371–382

    Article  PubMed  CAS  Google Scholar 

  • Yamazoe Y, Shimada M, Murayama N, Kawano S, Kato R (1986b) The regulation by growth hormone of microsomal testosterone 6/3-hydroxylase in male rat livers. J Biochem (Tokyo) 100: 1095–1097

    CAS  Google Scholar 

  • Yamazoe Y, Shimada M, Murayama N, Kato R (1987) Suppression of levels of phenobarbital-inducible rat liver cytochrome P-450 by pituitary hormone. J Biol Chem 262: 7423–7428

    PubMed  CAS  Google Scholar 

  • Yamazoe Y, Abu-Zeid M, Yamauchi K, Murayama N, Kato R (1988a) Enhancement by alloxan-induced diabetes of the rates of metabolic activation of three pyrolysate carcinogens via increase in the P-448-H content in rat liver. Biochem Pharmacol 37: 2503–2506

    Article  PubMed  CAS  Google Scholar 

  • Yamazoe Y, Murayama N, Shimada M, Yamauchi K, Nagata K, Imaoka S, Funae Y, Kato R (1988b) A sex-specific form of cytochrome P-450 catalyzing propoxycoumarin O-depropylation and its identity with testosterone 6(3-hydroxylase in untreated rat livers: reconstitution of the activity with microsomal lipids. J Biochem (Tokyo) 104: 785–790

    CAS  Google Scholar 

  • Yamazoe Y, Murayama N, Shimada M, Imaoka S, Funae Y, Kato R (1989a) Suppression of hepatic levels of an ethanol-inducible P-450DM/j by growth hormone: relationship between the increased level of P-450DM/j and depletion of growth hormone in diabetes. Mol Pharmacol 36: 716–722

    PubMed  CAS  Google Scholar 

  • Yamazoe Y, Murayama N, Shimada M, Kato R (1989b) Suppression of hepatic levels of phenobarbital-inducible P-450b and P-450e, and other neonatal P-450s in hypophysectomized rats by thyroid hormone. Biochem Biophys Res Commun 160: 609–614

    Article  PubMed  CAS  Google Scholar 

  • Yamazoe Y, Murayama N, Shimada M, Yamauchi K, Kato R (1989c) Cytochrome P450 in livers of diabetic rats: regulation by growth hormone and insulin. Arch Biochem Biophys 268: 567–575

    Article  PubMed  CAS  Google Scholar 

  • Yamazoe Y, Shimada M, Murayama N, Nagata K, Kato R (1989d) Yenobiotic Metabolism and Disposition. In: Kato R, Estabrook RW, Cayen MN (eds) Proceedings of the 2nd International ISSX Meeting. Taylor and Francis, London, pp 37–44

    Google Scholar 

  • Yamazoe Y, Ling X, Murayama N, Gong D, Nagata K, Kato R (1990) Modulation of hepatic level of microsomal testosterone 7a-hydroxylase, P-450a (P450IIA), by thyroid hormone and growth hormone in rat liver. J Biochem (Tokyo) 108: 599–603

    CAS  Google Scholar 

  • Yoshioka H, Lindberg R, Wong G, Ichikawa T, Itakura T, Burkhart B, Negishi M (1990) Characterization and regulation of sex-specific mouse steroid hydroxylase genes. Can J Physiol Pharmacol 68: 754–761

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. R. Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Yamazoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pharmacology, MC 1505, University of Connecticut Health Center, 263 Farmington Avenue, 06030, Farmington, CT, USA

    John B. Schenkman Ph.D.

  2. Institut für Toxikologie, Gesellschaft für Strahlen- und Umweltforschung mbH, Ingolstädter Landstr. 1, W-8042, Neuherberg, Fed. Rep. of Germany

    Helmut Greim M.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1993 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kato, R., Yamazoe, Y. (1993). Hormonal Regulation of Cytochrome P450 in Rat Liver. In: Schenkman, J.B., Greim, H. (eds) Cytochrome P450. Handbook of Experimental Pharmacology, vol 105. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-77763-9_29

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-77763-9_29

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-77765-3

  • Online ISBN: 978-3-642-77763-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation