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PMID: 15365655 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Effects of growth hormone deficiency and rhGH replacement therapy on the 6beta-hydroxycortisol/free cortisol ratio, a marker of CYP3A activity, in growth hormone-deficient children.

European journal of clinical pharmacology ·Vol. 60 ·No. 8 ·2004-10-00 ·Pages 559-64

Sinués B, Mayayo E, Fanlo A, Mayayo E, Bernal ML, Bocos P, Bello E, Labarta JI, Ferrández-Longás A

Abstract

To determine the effect of both growth hormone deficiency (GHD) and rhGH replacement therapy on CYP3A activity as well as the potential influence of gender. The sample consisted of 35 GHD children (16 males and 19 females), aged 2.9-13.1 years, and a control group of 35 healthy children matched for age and sex. The urinary ratio 6beta-hydroxycortisol/free cortisol was used as a marker of CYP3A activity. In patients, urine samples were collected at two times, prior to starting rhGH replacement treatment and 30 days after beginning therapy. A significantly higher metabolic activity in GHD children was observed in relation to controls ( P=0.0001) without sex differences. Paired comparisons demonstrated a sexually dimorphic effect of rhGH therapy on the CYP3A activity. While boys displayed a significant decrease ( P=0.003), girls showed no significantly different values of CYP3A marker ( P>0.05). Unpaired comparison between controls and GHD children after therapy demonstrated absence of significant differences in boys ( P>0.05) and a strikingly higher activity in girls ( P=0.0001). The data suggests that: (a) GHD in children increases CYP3A activity in a non-sex-dependent manner, (b) rhGH treatment for 30 days to GHD children results in a sexually dimorphic effect on CYP3A activity, with a significant decrease in males toward normalization in relation to controls and non-significant changes in females. The results of this study may have important clinical implications for GHD children, since changes in CYP3A activity importantly affect the metabolism of both steroid hormones and CYP3A substrate drugs.

MeSH Terms
Adolescent Case-Control Studies Child Child, Preschool Cytochrome P-450 Enzyme System/genetics Dwarfism, Pituitary/drug therapy,genetics,metabolism,urine Female Human Growth Hormone/administration & dosage,deficiency,therapeutic use Humans Hydrocortisone/analogs & derivatives,urine Male Recombinant Proteins/administration & dosage,therapeutic use
Chemicals
Recombinant Proteins Human Growth Hormone 6 beta-hydroxycortisol Cytochrome P-450 Enzyme System Hydrocortisone
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Sinués Blanca
Clinical Pharmacology Unit, Medicine School, University of Zaragoza, Domingo Miral s/n, 50009, Zaragoza, Spain. bsinues@unizar.es
Mayayo Esteban
Fanlo Ana
Mayayo Esteban
Bernal María L
Bocos Pilar
Bello Elena
Labarta Jose I
Ferrández-Longás Angel
References (47)
47 references, click to expand
  1. The genetic determinants of the CYP3A5 polymorphism.
    Pharmacogenetics. 2001 Dec;11(9):773-9 PMID: 11740341
  2. Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes.
    Chem Res Toxicol. 1991 Jul-Aug;4(4):391-407 PMID: 1912325
  3. Growth hormone replacement therapy induces codeine clearance.
    Eur J Clin Invest. 2002 Jul;32(7):507-12 PMID: 12153551
  4. Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase.
    J Biol Chem. 1997 Jul 11;272(28):17694-702 PMID: 9211920
  5. Expression of cytochrome P-450 isozymes in the liver of hypophysectomized rats. Evidence for different regulation mechanisms concerning P450IIB and P450IIIA subfamilies.
    Eur J Biochem. 1988 Nov 15;177(3):597-604 PMID: 3197720
  6. Growth hormone treatment increases cytochrome P450-mediated antipyrine clearance in man.
    J Clin Endocrinol Metab. 1996 May;81(5):1999-2001 PMID: 8626872
  7. Fluconazole: a potent inhibitor of cytochrome P-450-dependent drug-metabolism in mice and humans in vivo. Comparative study with ketoconazole.
    Chem Pharm Bull (Tokyo). 1992 May;40(5):1247-51 PMID: 1394641
  8. Genetic contribution to variable human CYP3A-mediated metabolism.
    Adv Drug Deliv Rev. 2002 Nov 18;54(10):1271-94 PMID: 12406645
  9. A quantitative estimation of growth hormone secretion in normal man: reproducibility and relation to sleep and time of day.
    J Clin Endocrinol Metab. 1992 Jun;74(6):1441-50 PMID: 1592892
  10. Urinary excretion of 6 beta-hydroxycortisol as an in vivo marker for CYP3A induction: applications and recommendations.
    Clin Pharmacol Ther. 1998 Jun;63(6):617-22 PMID: 9663175
  11. Effect of growth hormone on hepatic cytochrome P450 activity in healthy elderly men.
    Clin Pharmacol Ther. 2002 Mar;71(3):162-8 PMID: 11907490
  12. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate.
    Drug Metab Dispos. 1998 Jul;26(7):609-16 PMID: 9660842
  13. Urinary 6 beta-hydroxycortisol in humans: analysis, biological variations, and reference ranges.
    Clin Biochem. 1995 Feb;28(1):49-54 PMID: 7720227
  14. Regulatory mechanisms of growth hormone secretion are sexually dimorphic.
    J Clin Invest. 1998 Jul 1;102(1):153-64 PMID: 9649569
  15. Effect of growth hormone therapy in growth hormone-deficient children on cytochrome P-450-dependent 3-N-demethylation of caffeine as measured by the caffeine 13CO2 breath test.
    Dev Pharmacol Ther. 1989;12(2):90-5 PMID: 2496962
  16. Growth hormone regulation of male-specific rat liver P450s 2A2 and 3A2: induction by intermittent growth hormone pulses in male but not female rats rendered growth hormone deficient by neonatal monosodium glutamate.
    Mol Pharmacol. 1995 Nov;48(5):790-7 PMID: 7476908
  17. Down-regulation of liver JAK2-STAT5b signaling by the female plasma pattern of continuous growth hormone stimulation.
    Mol Endocrinol. 1999 Feb;13(2):213-27 PMID: 9973252
  18. Gender differences in drug metabolism regulated by growth hormone.
    Int J Biochem Cell Biol. 1995 Jan;27(1):9-20 PMID: 7757886
  19. CYP3A5 variant allele frequencies in Dutch Caucasians.
    Clin Chem. 2002 Oct;48(10):1668-71 PMID: 12324482
  20. Regulation of cytochrome P450 genes: molecular mechanisms.
    Pharmacogenetics. 1993 Feb;3(1):51-7 PMID: 8387380
  21. Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein. Proposed role as an intracellular regulator of male-specific liver gene transcription.
    J Biol Chem. 1995 Jun 2;270(22):13262-70 PMID: 7768925
  22. Comparison of urinary 6-beta-cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity.
    Clin Pharmacol Ther. 1992 Sep;52(3):265-73 PMID: 1526083
  23. Gender differences in rat hepatic CYP2C gene expression--regulation by growth hormone.
    Growth Horm IGF Res. 1998 Apr;8 Suppl B:61-7 PMID: 10990136
  24. Role of human microsomal and human complementary DNA-expressed cytochromes P4501A2 and P4503A4 in the bioactivation of aflatoxin B1.
    Cancer Res. 1994 Jan 1;54(1):101-8 PMID: 8261428
  25. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.
    J Pharmacol Exp Ther. 1994 Jul;270(1):414-23 PMID: 8035341
  26. A single dose of methadone inhibits cytochrome P-4503A activity in healthy volunteers as assessed by the urinary cortisol ratio.
    Br J Clin Pharmacol. 2001 Apr;51(4):350-4 PMID: 11318772
  27. A sex-specific form of cytochrome P-450 catalyzing propoxycoumarin O-depropylation and its identity with testosterone 6 beta-hydroxylase in untreated rat livers: reconstitution of the activity with microsomal lipids.
    J Biochem. 1988 Nov;104(5):785-90 PMID: 3266213
  28. A distribution method for analysing the baseline of pulsatile endocrine signals as exemplified by 24-hour growth hormone profiles.
    Clin Endocrinol (Oxf). 1991 Sep;35(3):245-52 PMID: 1742882
  29. Effect of growth hormone on human drug metabolism: time course and substrate specificity.
    Pediatr Pharmacol (New York). 1980;1(1):63-70 PMID: 7346733
  30. Effects of testosterone and growth hormone treatment on hepatic microsomal P450 expression in the diabetic rat.
    Mol Pharmacol. 1990 Jan;37(1):119-29 PMID: 2105452
  31. Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans.
    Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E1008-15 PMID: 12376329
  32. Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat.
    Endocrinology. 1976 Mar;98(3):562-70 PMID: 1261487
  33. Hepatic steroid hydroxylating enzymes are controlled by the sexually dimorphic pattern of growth hormone secretion in normal and dwarf rats.
    FASEB J. 1992 Jan 6;6(2):711-8 PMID: 1537461
  34. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.
    Clin Pharmacokinet. 2000 Jan;38(1):41-57 PMID: 10668858
  35. Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes.
    J Clin Endocrinol Metab. 1998 Jul;83(7):2411-6 PMID: 9661620
  36. Signaling by the cytokine receptor superfamily: JAKs and STATs.
    Trends Biochem Sci. 1994 May;19(5):222-7 PMID: 8048164
  37. Adult male-specific and neonatally programmed rat hepatic P-450 forms RLM2 and 2a are not dependent on pulsatile plasma growth hormone for expression.
    J Biol Chem. 1988 Aug 15;263(23):11396-406 PMID: 3403535
  38. Impairment of CYP3A4 capacity in patients receiving danazol therapy: examination on oxidative cortisol metabolism.
    Horm Metab Res. 2001 Oct;33(10):628-30 PMID: 11607885
  39. Cytochrome P450 3A: ontogeny and drug disposition.
    Clin Pharmacokinet. 1999 Dec;37(6):485-505 PMID: 10628899
  40. Consequences of overexpression of growth hormone in transgenic mice on liver cytochrome P450 enzymes.
    Biochem Pharmacol. 1998 May 1;55(9):1481-7 PMID: 10076541
  41. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients.
    J Clin Invest. 1989 Feb;83(2):688-97 PMID: 2913056
  42. Cytochromes P450 and metabolism of xenobiotics.
    Cell Mol Life Sci. 2001 May;58(5-6):737-47 PMID: 11437235
  43. Developmental changes in the constitutive and inducible expression of cytochrome P450 3A2.
    Biochem Pharmacol. 1997 Oct 1;54(7):841-6 PMID: 9353139
  44. Continuous infusion of growth hormone feminizes hepatic steroid metabolism in the rat.
    Endocrinology. 1981 Jun;108(6):2103-8 PMID: 7227299
  45. Effect of human growth hormone on amobarbital metabolism in children.
    Clin Pharmacol Ther. 1978 Aug;24(2):213-8 PMID: 679599
  46. Age- and sex-related differences in episodic growth hormone secretion in the rat.
    Endocrinology. 1979 Aug;105(2):555-60 PMID: 572295
  47. Growth hormone regulation and developmental expression of rat hepatic CYP3A18, CYP3A9, and CYP3A2.
    Biochem Pharmacol. 2000 May 15;59(10):1277-87 PMID: 10736428
Article Info
Journal
European journal of clinical pharmacology
Abbr.
Eur J Clin Pharmacol
ISSN
0031-6970
DOI
10.1007/s00228-004-0806-4
Email
bsinues@unizar.es
Published
2004-10-00
Epub
2004-00-07
Pages
559-64
Language
English
Region
Germany
NLM ID
1256165
Subset
IM
External Links
PubMed source DOI: 10.1007/s00228-004-0806-4 View journal details
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