Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polymorphisms in genes can lead to differences in the level of susceptibility of individuals to potentially adverse effects of environmental influences, such as chemical exposure, on prenatal development or male or female reproductive function. We have reviewed the literature in this area, with the caveat that papers involving straight gene knock-outs in experimental animals, without a clear human relevance, were largely excluded. This review represents current knowledge in this rapidly moving field, presenting both human epidemiological and animal data, where available. Among the polymorphic genes and environmental interactions discussed with respect to prenatal development are those for P-glycoprotein (multidrug resistance protein) and the avermectins; methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, and dietary folic acid; transforming growth factor alpha (TGFalpha) and cigarette smoke; and alcohol dehydrogenase (ADH) and cytochrome P-450 (CYP) 2E1 in association with alcohol consumption. Effects on male reproduction attributable to gene-environment interaction involve infertility seen as a result of either organophosphorous (OP) pesticide interaction with the polymorphic paraoxonase (PON1) gene or antiandrogenic agent interaction with the androgen receptor (AR). MTHFR, folate metabolism, and dietary folic acid are also considered in conjunction with preeclampsia and early pregnancy loss, and the effect of the interaction of glutathione S-transferase (GST) with exposure to benzene or cigarette smoke on pregnancy maintenance is explored. As a conclusion, we offer a discussion of lessons learned and suggested research needs.
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PMID:Gene-environment interactions: a review of effects on reproduction and development. 1560 83

Throughout spermatogenesis, leptotene spermatocytes traverse the blood-testis barrier (BTB) to enter the adluminal compartment of the seminiferous epithelium for continued development. At the same time, the integrity of the BTB, which is constituted by co-existing tight junctions (TJ), basal ectoplasmic specializations (basal ES) and desmosome-like junctions, must be maintained since a breach in barrier function can result in spermatogenic arrest and even infertility. There is evidence to suggest that drug transporters may function at the BTB, but little is known about how they contribute to spermatogenesis. In this study, we investigate the role of P-glycoprotein (P-gp), a drug efflux pump, in BTB dynamics. A survey by RT-PCR revealed several transporter genes to be expressed by the testis, including Mdr1 (gene symbol for P-gp), Mrp1, Abcc5 and Slc15a1. It was also demonstrated that P-gp localizes to the BTB in all stages of the seminiferous epithelial cycle in the adult rat testis, as well as to the Sertoli cell-elongated spermatid interface in stages VII and VIII. We continued our study by examining the levels of several transporters in the testis following oral administration of Adjudin, a compound known to affect Sertoli-germ cell adhesion. In this experiment, the steady-state levels of P-gp, MRP1, ABCG1 and SLC15A1 were all found to increase by several-fold within hours of Adjudin treatment during junction restructuring. More importantly, an increase in P-gp association with TJ proteins (e.g., occludin, claudin-11 and JAM-A) was noted when testis lysates from Adjudin-treated rats were used for co-immunoprecipitation experiments, suggesting that P-gp may enhance BTB function during Sertoli-germ cell junction restructuring.
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PMID:Drug transporter, P-glycoprotein (MDR1), is an integrated component of the mammalian blood-testis barrier. 1972 Jan 56

Infertility is a common problem affecting one in six couples, and in 30% of infertile couples, the male factor is a major cause due to defective sperm quality. P-glycoprotein (P-gp), a product of the MDR1 (ABCB1) gene, may be a link between genetic and environmental factors contributing to the development of male infertility because pesticides (P-gp substrates) are well established factors of male infertility. The aim of the present study was to examine the effect of the MDR1 gene 3435C>T polymorphism on male infertility. In total, 162 male patients undergoing semen analysis due to initial infertility workup were included in the study. The control group consisted of 191 healthy males with proven fertility. MDR1 3435C>T genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Assessment of MDR1 genotypes among the infertile men showed that 17.9% of subjects were carriers of the CC genotype, 58.0% were CT and 24.1% were TT. Among fertile men, 30.4% of subjects were characterised by the CC genotype, 49.7% were CT and 19.9% were TT. In addition, the frequency of carriers of at least one T allele (i.e., CT and TT genotypes) among infertile and fertile subjects was 82.1% and 69.6%, respectively. The risk of infertility was significantly elevated by two-fold in individuals carrying at least one T allele (CT and TT genotypes: p = 0.009, OR = 2.00, 95% CI: 1.20-3.32). Furthermore, this elevated risk was still found when considering each of the CT and TT genotypes alone (TT genotype: p = 0.027, OR = 2.05, 95% CI: 1.09-3.86; CT genotype: p = 0.013, OR = 1.98, 95% CI: 1.16-3.36). This preliminary report suggests that P-gp may play some role in male infertility, mediating detrimental effects of environmental factors.
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PMID:Association of the MDR1 (ABCB1) gene 3435C>T polymorphism with male infertility. 1981 51

Infertility affects 1 in 6 couples and approximately 1 in 25 men. Male factor infertility is a major cause of spermatogenic anomalies, the causes of which are largely unknown. Impaired repro-ductive functions in men might result from physiological, genetic, and/or environmental factors such as xenobiotics. The multi-drug re-sistance1 (MDR1) gene encodes a P-glycoprotein which has a role in the active transport of various substrates providing protection of somatic cells from potentially toxic substances, including xenobi-otics. MDR1 is highly expressed at the luminal surface of capillary endothelial cells, and is expressed in Leydig cells, testicular mac-rophages, and Sertoli cells. We performed genotype and haplotype analyses of MDR1 in 192 infertile and 102 fertile Turkish men for the genetic markers C1236T and C3435T, using polymerase chain reaction-restriction fragment length polymorphism analysis. In the overall population, correlations were analyzed in all genotype mod-els. We found that the C3435T polymorphism TT vs CT genotypes showed statistically significant differences in their association with infertility (P = 0.045), and that the CT genotype was associated with high sperm DNA damage (P = 0.02), suggesting that the CT genotype might be a susceptibility factor for infertility. Additionally, the T-T haplotype was significantly more frequent in the control group (13.2 vs 6.5%; odds ratio = 0.459, 95%CI = 0.259-0.814, P = 0.006). This study showed that MDR1 might have a role in male infertility. Fur-ther research in large cohorts with different populations is required to clarify the role of MDR in male fertility.
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PMID:Association of MDR1 C3435T and C1236T single nucleotide polymorphisms with male factor infertility. 2612 37