The PXR rs7643645 Polymorphism Is Associated with the Risk of Higher Prostate-Specific Antigen Levels in Prostate Cancer Patients

<div><p>Levels of enzymes that determine testosterone catabolism such as CYP3A4 have been associated with prostate cancer (PCa) risk. Although some studies have related <i>CYP3A4*1B</i> allele, a gene polymorphism that modifies CYP3A4 expression level, with PCa risk, others have failed, suggesting that additional genetic variants may be involved. Expression of CYP3A4 is largely due to the activation of Pregnane X Receptor (PXR). Particularly, rs2472677 and rs7643645 <i>PXR</i> polymorphisms modify CYP3A4 expression levels. To evaluate whether <i>PXR-HNF3β</i>/T (rs2472677), <i>PXR-HNF4/G</i> (rs7643645), and <i>CYP3A4*1B</i> (rs2740574) polymorphisms are associated with PCa a case control-study was performed. The multiple testing analysis showed that the <i>PXR-HNF4/G</i> polymorphism was associated with higher levels of prostate-specific antigen (PSA) in patients with PCa (OR = 3.99, p = 0.03). This association was stronger in patients diagnosed at the age of 65 years or older (OR = 10.8, p = 0.006). Although the <i>CYP3A4*1B/*1B</i> genotype was overrepresented in PCa patients, no differences were observed in the frequency of this and <i>PXR-HNF3β</i>/T alleles between controls and cases. Moreover, no significant association was found between these polymorphisms and PSA, Gleason grade, or tumor lymph node metastasis.</p></div

Association of <i>PXR-HNF4</i> genotype and clinical characteristics in patients diagnosed at the age of ≥65.

<p>Association of <i>PXR-HNF4</i> genotype and clinical characteristics in patients diagnosed at the age of ≥65.</p

Distribution of <i>CYP3A4</i> and <i>PXR</i> genotypes.

<p>^*x² test.</p>&<p>Fisher's exact test.</p><p>n, No. of subjects.</p

Association of <i>CYP3A4</i> genotype and clinical characteristics in patients diagnosed at the age of ≥65.

<p>PSA, prostatic-specific antigen. TNM, tumor lymph nodes metastasis.</p>a<p>Comparing those with <i>*1A</i><b><i>/*</i></b><i>1A versus</i> those with</p><p><i>*1B</i><b><i>/*</i></b><i>1B</i> and <i>*1A</i><b><i>/*</i></b><i>1B</i> genotypes (dominant model).^* Logistic model.</p><p>n, No. of subjects.</p

Modifications in Vaginal Microbiota and Their Influence on Drug Release: Challenges and Opportunities

Vaginal drug delivery represents an attractive alternative to achieve local and systemic effects due to the high contact surface exposed, the mucoadhesion of the epithelium, and the high innervation that facilitates the absorption of drugs into the bloodstream. However, despite the confinement of the vaginal cavity, it is an organ with a highly variable microenvironment. Mechanical alterations such as coitus, or chemical changes such as pH and viscosity, modify the release of drugs. In addition, changes in vaginal microbiota can influence the entire vaginal microenvironment, thus determining the disposition of drugs in the vaginal cavity and decreasing their therapeutic efficacy. Therefore, the influence of microorganisms on vaginal homeostasis can change the pre-established scenario for the application of drugs. This review aims to provide an explanation of normal vaginal microbiota, the factors that modify it, its involvement in the administration of drugs, and new proposals for the design of novel pharmaceutical dosage forms. Finally, challenges and opportunities directed toward the conception of new effective formulations are discussed

Distribution of combined <i>CYP3A4</i> and <i>PXR</i> allelic variants.

<p>^*x² test.</p>&<p>Fisher's exact test. NA, not applicable.</p><p>n, No. of subjects.</p

Characteristics of the study subjects.

<p>PSA, prostate specific antigen. DRE, digital rectal examination.</p><p>^*x² test.</p>&<p>Fisher exact when expected value<5.</p>α<p>p values were obtained using t⁻ test or one way ANOVA test as applied.</p

<i>PXR-HNF4</i>/G variant is associated with higher PSA levels.

<p>Individuals from the case group were genotyped for <i>PXR-HNF4</i>/G variant and divided in groups according to their genotype: 20 individuals corresponded to homozygous <i>PXR-HNF4-WT/WT</i>, 45 corresponded to heterozygous <i>PXR-HNF4-WT/G</i>, and 28 corresponded to <i>PXR-HNF4-G/G</i>. The data were analyzed by using the Mann Whitney U test. Horizontal line indicates the median. <i>WT/WT vs WT/G</i>, p = 0.05; <i>WT/WT vs G/G</i>, p = 0.02.</p

Association between <i>CYP3A4</i> (A), <i>PXR-HNF3β</i> (B), and <i>PXR-HNF4</i> (C) genotypes and clinical characteristics among cases.

<p>Case group was categorized as follows: PSA two groups, (cut point, 10 ng/mL); Gleason grade two groups (cut point, 7); and TNM two groups (TNM≤2 and TNM≥3). ORs were calculated as an estimate of relative risk and 95% confidence intervals (CIs) were calculated using a bivariate logistic model. PSA, prostate-specific antigen. TNM, tumor lymph nodes metastasis. *p = 0.03.</p