PHARMACOGENETICS
Blanca Sinue
´
s Æ Esteban Mayayo Æ Ana Fanlo
Esteban Mayayo JR Æ Marı
´
a L. Bernal Æ Pilar Bocos
Elena Bello Æ Jose I. Labarta Æ Angel Ferra
´
ndez-Longa
´
s
Effects of growth hormone deficiency and rhGH replacement therapy
on the 6b-hydroxycortisol/free cortisol ratio, a marker of CYP3A activity,
in growth hormone-deficient children
Received: 23 March 2004 / Accepted: 24 June 2004 / Published online: 7 September 2004
Ó Springer-Verlag 2004
Abstract Objective: To determine the effect of both
growth hormone deficiency (GHD) and rhGH replace-
ment therapy on CYP3A activity as well as the potential
influence of gender.
Methods: The sample consisted of 35 GHD children (16
males and 19 females), aged 2.9–13.1 years, and a con-
trol group of 35 healthy children matched for age and
sex. The urinary ratio 6b-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.
Results: 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 signifi-
cantly different values of CYP3A marker (P>0.05).
Unpaired comparison between controls and GHD chil-
dren after therapy demonstrated absence of significant
differences in boys (P>0.05) and a strikingly higher
activity in girls (P=0.0001).
Conclusions: The data suggests that: (a) GHD in chil-
dren increases CYP3A activity in a non-sex-dependent
manner, (b) rhGH treatment for 30 days to GHD chil-
dren 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.
Keywords rhGH therapy Æ CYP3A4 activity Æ
GH-deficiency
Introduction
CYP3A is the predominant constitutive hepatic cyto-
chrome P
450
(CYP) in humans and is responsible for
approximately 60% of the total drug oxidations [1].
Hydroxylations of endogenous steroids, such as testos-
terone and estradiol, are catalyzed by CYP3A [2]. Bio-
activation of genotoxicants aflatoxin-B1 [3] and
heterocyclic amines [4] is also produced by this P
450
isoform. CYP3A activity is characterized by its inter-
individual variability, which importantly accounts for
the variable pharmacokinetics of its substrates [5].
Changes in activity of this cytochrome, produced by
inducers or inhibitors, are known to cause important
clinical consequences in terms of either efficacy or tox-
icity [6, 7].
B. Sinue
´
s(&)
Clinical Pharmacology Unit, Medicine School,
University of Zaragoza, Domingo Miral s/n,
50009 Zaragoza, Spain
E-mail: bsinues@unizar.es
Tel.: +34-76-761698
Fax: +34-76-761700
E. Mayayo Æ J. I. Labarta Æ A. Ferra
´
ndez-Longa
´
s
Pediatric Endocrinology Unit,
University Hospital ‘‘Miguel Servet’’,
50009 Zaragoza, Spain
P. Bocos
Laboratory of Biochemistry,
University Hospital ‘‘Miguel Servet’’,
50009 Zaragoza, Spain
A. Fanlo Æ E. M. JR Æ M. L. Bernal
Department of Pharmacology,
University of Zaragoza, Zaragoza, Spain
E. Bello
Center for Pediatric Healthcare ‘‘Arrabal’’,
Zaragoza, Spain
Eur J Clin Pharmacol (2004) 60: 559–564
DOI 10.1007/s00228-004-0806-4