Elsevier

Steroids

Volume 75, Issue 12, December 2010, Pages 1024-1032
Steroids

Cytochrome P450 3A gene variation, steroid hormone serum levels and prostate cancer––The Rotterdam Study

https://doi.org/10.1016/j.steroids.2010.07.001Get rights and content

Abstract

Purpose

To study if polymorphisms in genes encoding for CYP3A enzymes, that play a role in steroid hormone metabolism, affect steroid hormone serum levels and prostate cancer incidence or mortality.

Methods

3048 male participants of The Rotterdam Study were included. Prostate cancer cases and non-cases were studied for differences in baseline hormone levels with Student's t-test. General linear models were performed on different random subsets of hormone levels to study associations with genotype. Cox’ proportional hazard models were used to study prostate cancer incidence and mortality among genotypes.

Results

Both DHEAS sulphate as free-testosterone were significantly increased at baseline in males who developed a prostate cancer within the study period. CYP3A4 G-allele carriage was associated with lower levels of estrone sulphate (p = 0.005) and higher levels of estradiol (p = 0.04) compared to non-carriers. CYP3A5 A-allele carriage was associated with increased levels of estrone sulphate (p = 0.02). CYP3A7 G-allele carriage was associated with the highest number of significant differences in steroid hormone levels. Carriers of the allele resulting in continued enzyme expression during adulthood had decreased levels of dehydroepiandrosterone (DHEA) sulphate (p = 0.05), androstenedione (p = 0.006), estrone (p = 0.0001) and estrone sulphate (p = 0.003) compared to mean levels of these hormones in homozygous wild type carriers. CYP3A43 genotype was not associated with any of the studied hormone levels. However, carriers of the CYP3A43 G-allele showed a significant 5-fold increase in mortality among early onset diagnosed prostate cancers.

Conclusion

Increased levels of free testosterone and DHEA sulphate were associated with prostate cancer incidence along the study period. Primarily the amount of CYP3A7 expression seemed to affect steroid hormone levels. Nevertheless, testosterone, a precursor of the prostate growth and differentiation stimulating dehydrotestosterone, was not influenced by CYP3A genotype. In line with this, no significant associations were observed for CYP3A genotypes and prostate cancer incidence.

Research highlights

▶ Free testosterone and DHEA sulphate levels are significantly increased in males before the diagnosis of prostate cancer. ▶ CYP3A7 G-allele is associated with steroid hormone levels. ▶ CYP3A seems to have no influence on testosterone or dehydroepiandrosterone. ▶ Prostate cancer incidence was not influenced by CYP3A genotypes.

Introduction

An enumeration of evidence supports the role of androgens in prostate cancer risk [1], [2]. Circulating levels of androgens have been reported as being highest in African-American men who experience the highest incidence of prostate cancer and lowest in Chinese men with the lowest prostate cancer incidence; castration at an early age prevents prostate cancer; aging is a major risk factor, suggesting that duration of exposure to androgens might be important; serum levels of testosterone metabolites such as dehydrotestosterone (DHT) correlate with prostate cancer and its growth and differentiation; androgen ablation in hormone receptor positive prostate cancer patients reduces tumor size and disease burden. Therefore, candidate genes for the association with prostate cancer are those that are implicated in androgen production and metabolism. Numerous molecular genetic studies have been performed on polymorphic genes such as the androgen receptor (AR), prostate specific antigen (PSA), 5α-reductase type II (SRD5A2), cytochrome P450c17α (CYP17) and a putative hereditary prostate cancer susceptibility gene (ELAC2) [3].

Another group of candidate genes are those, which encode for the cytochrome P450 3A (CYP3A) enzyme subfamily that seems to determine bioavailability of testosterone as well [4]. CYP3A is the major subfamily of cytochrome P450 in the human liver and metabolizes many drugs, xenobiotics and endogenous compounds. The genetic coding for this subfamily consists of a cluster of four CYP3A genes on chromosome 7q21.1 (CYP3A4, CYP3A5, CYP3A7 and CYP3A43) each of which contains 13 exons. They share 70–90% of metabolic properties, but are differentially regulated [5], [6]. CYP3A4, CYP3A5 and CYP3A43 enzymes catalyze 2β-, 6β- and 15β-hydroxylation of mainly testosterone and are involved in the formation of less biologically active metabolites [7], [8]. CYP3A7 has a catalytic activity for 16α-hydroxylation of estrone, dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) [9], [10] (Fig. 1).

Polymorphic expression of the four genes has been studied for alterations of biological functions and prostate cancer risk. For a promoter variant (A-293 G) of CYP3A4, designated as *1B, functionality remains controversial (Table 1). Although epidemiologic studies provide evidence for a decreased activity, with reduced conversion of testosterone to its less bioactive metabolites [1], [11], [12], [13], [14], [15], molecular genetic in vitro studies concluded for a long time that no biological meaningful effects could be found [16], [17], [18], [19], [20], [21], [22]. Nevertheless, a re-calculation of the data of Westlind et al. [16] by Rebbeck showed a 2.9-fold increased 6β-hydroxylase activity in CYP3A4*1B carriers compared to non-carriers [23] that was reproduced by others as well [24] and almost all studies observed elevations in expression levels of the gene in variant carriers. Among Caucasians, 80% of the population carries the CYP3A5*3 variant that results in aberrantly spliced mRNA with a premature stop codon. The decreased activity might result in a higher bioavailability of testosterone. It has originally been thought that CYP3A7 was exclusively expressed during fetal life, but a replacement of a part of the promoter (*1C) with a sequence identical with the same region in the CYP3A4 promoter, leads to a continued expression in adulthood. This higher activity might shunt DHEA to testosterone. A missense mutation in exon 10 in the CYP3A43 gene (*3) was hypothesized to decrease the conversion of testosterone to 6β-hydroxytestosterone, leaving more testosterone available for the conversion to the active form, dehydrotestosterone [25].

The aim of this study was to clarify the role of polymorphic CYP3A expression in the regulation of steroid hormone serum levels in males and to study the association between CYP3A gene variation and prostate cancer incidence and mortality.

Section snippets

Setting

Data were obtained from The Rotterdam Study, a population-based prospective cohort study on prevalence, incidence and risk factors for chronic disabling diseases in the elderly. It started with a baseline interview between July 1989 and July 1993. All inhabitants of the Rotterdam suburb Ommoord (a completely Caucasian part of Rotterdam), aged 55 years and older, were invited. Of the 10,275 eligible subjects, 7983 (78%) agreed to participate [26]. 3105 of them were males. The Medical Ethics

Results

Individuals of whom the genotype was unknown (according to the genotype under assay, this ranged from 437 to 597 individuals) were on average older, relatively more frequently smoker, and had a shorter follow-up time than those for whom genotype data were available. All SNPs were in HWE (Table 1). Table 2 presents baseline characteristics of the study cohort.

Both free-testosterone (0.25 ± 0.1 nmol/L vs 0.29 ± 0.1 nmol/L; p = 0.04) as DHEA sulphate (4.28 ± 2.8 μmol/L vs 5.10 ± 4.2 μmol/L; p = 0.04) levels were

Discussion

This population-based study was subdivided into three parts. In the first part, mean steroid hormone levels at baseline were compared between males who did and did not develop a prostate cancer along the study period. Males with a prostate cancer seemed to have significantly increased levels of DHEA sulphate and free testosterone, which is in line with common knowledge about pathogeneses. The second part included association studies on cytochrome P450 3A genotypes and these steroid hormone

Conflicts of interest

None.

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    Address for reprint: Department of Epidemiology & Biostatistics, Erasmus Medical Center, Dr. Molewaterplein 50, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 4087489; fax: +31 10 4089382.

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