Calcif Tissue Int (2007) 80:154 159 DOI: 10.1007/s00223-006-0227-8
CYP3A7*1C Polymorphism, Serum Dehydroepiandrosterone Sulfate Level, and Bone Mineral Density in Postmenopausal Women K. Ba´csi, J. P. Ko´sa, G. Borgulya, B. Balla, A´. Laza´ry, Z. Nagy, C. Horva´th, G. Speer, P. Lakatos 1st Department of Medicine, Semmelweis University Budapest, Budapest 1083 Kora´nyi S. u 2/a, Hungary
Received: 22 August 2006 / Accepted: 14 November 2006 / Online publication: 3 March 2007
Abstract. The CYP3A7 enzyme metabolizes some steroid hormones, including dehydroepiandrosterone sulfate (DHEAS). The age-related decline of serum DHEAS levels is believed to contribute to osteoporosis. Previously, the CYP3A7*1C polymorphism has been shown to cause a persistent high CYP3A7 enzyme activity, resulting in lower levels of DHEAS in men. We hypothesized that the CYP3A7*1C polymorphism might contribute to bone loss through decreased levels of serum DHEAS in postmenopausal women. Postmenopausal women (n = 319) were divided into two subgroups: 217 with osteoporosis and 102 healthy controls. Genotyping, serum DHEAS measurement, and osteodensitometry of the lumbar spine and femoral neck were carried out in all subjects. Homozygous CYP3A7*1C carriers had significantly lower BMD at the lumbar spine compared to wild types (T score )3.27 ± 1.02 in CYP3A7*1C homozygous mutants vs. )1.35 ± 1.53 in wild types, P = 0.041). This association remained significant after adjustment for menopausal age, serum DHEAS level, alcohol consumption, steroid intake, smoking habits, and previous fractures. No association was found between genotypes and serum DHEAS levels in the total study population or in the subgroups. Serum DHEAS levels correlated positively with bone mineral density at the lumbar spine (r = 0.59, P = 0.042) after correction for age. Our data suggest that the CYP3A7 polymorphism might have an influence on bone mass at the lumbar spine independently of serum DHEAS concentrations. Key words: Osteoporosis — Dehydroepiandrosterone sulfate — CYP3A7 — Bone mineral density — Genetic polymorphism
Cytochrome P)450 is a family of hemoproteins functioning in the oxidative metabolism of a variety of endogenous and exogenous substrates, including steroid hormones [1, 2]. Of these, the CYP3A subfamily of enzymes has been established as the most abundant P-450 in humans, representing about 30% of all hepatic P-450 [3]. CYP3A genes are localized in a cluster on chromo-
some 7q21 q22 [4] and consist of isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43 [5 8]. CYP3A7 is predominantly expressed in fetal liver, and its expression seems to be silenced shortly after birth. CYP3A7 mRNA was only 1.7% in adults compared with the fetus [9]. In case of a mutant CYP3A7 variant, CYP3A*1C, the enzyme expression level was at a higher level [10]. CYP3A7 catalyzes both the 16a-hydroxylation of dehydroepiandrosterone (DHEA) and its 3-sulfate, DHEA sulfate (DHEAS) [1]. It has also moderate activity for the 2-hydroxylation of 17b-estradiol and estrone, but it has distinct catalytic activity for the 16aand 6b-hydroxylation of estrone [11]. Other substrates are testosterone (2b-hydroxylation, 6b-hydroxylation) [12] and androstenedione (6b-hydroxylation) [6]. Smit et al. [13] found a significant difference in the amount of serum DHEAS level between wild-type and mutant allele carriers of the CYP3A7*1C genotype, suggesting persistence of the enzymatic activity of CYP3A7 during adult life (corresponding to the CYP3A7*1C allele), resulting in lower DHEAS levels. However, they could not detect such a relationship with estradiol, testosterone, or androstenedione. DHEAS is the most abundant estrogen and androgen precursor in postmenopausal women [14]. The progressive decline in serum DHEAS with increasing age is believed to contribute to age-related diseases, such as osteoporosis [15]. We hypothesized that the mutant CYP3A7 variant CYP3A7*1C may contribute to bone loss through decreased levels of DHEAS. The purpose of the current study was to investigate the associations among CYP3A7*1C alleles, DHEAS levels, and bone mineral density (BMD) in postmenopausal women.
Materials and Methods Patients
G. Speer, P. Lakatos contributed equally to this work Correspondence to: G. Speer; E-mail:
[email protected]
We examined 319 postmenopausal women, who were divided into two groups. Patients had age-related osteoporosis
K. Ba´csi et al.: CYP3A7*1C in Postmenopausal Women
155
Table 1a. Clinical characteristics, BMD and CYP3A genotypes of patients and controls Patients (n = 217) Clinical characteristics (mean ± SD or case number [%]) Age (years) 68.84±6.76 Menopausal age (years) 19.05±9.52 Height (cm) 155.58±7.04 Weight (kg) 68.49±11.13 BMI (kg/m2) 30.93±10.04 Smoker 30 (14%) Daily consumption of alcohol 23 (11%) History of steroid intake 5 (2%) History of fractures 70 (32%) Daily calcium intake (mg)b 628±75 BMD Lumbar spine Z score )0.60±1.13 Lumbar spine T score )2.15±1.15 Femoral neck Z score )0.23±0.74 Femoral neck T score )1.66±0.85 Genotype and hormone CYP3A7*1C allele frequency (%) 3.9 DHEAS (lmol/L) 2.04±1.20 a b
Controls (n = 102)
Total (n = 319)
Pa
55.59±8.52 5.27±7.07 162.88±6.44 74.78±13.82 35.44±13.66 21 (21%) 19 (19%) 11 (11%) 22 (22%) 636±90
64.62±9.60 14.83±10.88 157.68±7.62 70.30±12.27 32.23±11.36 51 (16%) 42 (13%) 16 (5%) 92 (28%) 631±95
