|Year : 2016 | Volume
| Issue : 2 | Page : 213-215
Microsomal epoxide hydrolase gene polymorphisms and susceptibility to prostate cancer: A systematic review
Department of Biotechnology and Molecular Medicine, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
|Date of Web Publication||6-Jan-2017|
Department of Biotechnology and Molecular Medicine, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana
Source of Support: None, Conflict of Interest: None
Microsomal epoxide hydrolase (mEH) is a crucial biotransformation enzyme that has capability to metabolize a large number of structurally divergent, highly reactive epoxides, and numerous environmentally exposed carcinogens. It catalyzes the conversion of xenobiotic epoxide compounds into more polar diol metabolites and may play important part of the enzymatic defense against adverse effects of foreign compounds. Most commonly, two functional polymorphisms affecting mEH enzyme activity have been identified: One in exon 3 and other in exon 4 of the mEH gene, which results in His113Tyr and Arg139His amino acid substitutions, respectively. Recent reports have shown that polymorphisms in mEH gene loci may an important risk factor for susceptibility of prostate cancers (PCs), worldwide, but inconsistent finding were also be illustrated. To the best of our knowledge, globally, there is no any systematic review has been published related to mEH gene polymorphisms and PC risk. Thus, in the current review, we have discussed the association between mEH gene polymorphisms, gene–environmental interaction, and PC risk.
Keywords: Gene polymorphism, gene–environmental interaction, gene-gene interaction, microsomal epoxide hydrolase, prostate cancer
|How to cite this article:|
Srivastava D. Microsomal epoxide hydrolase gene polymorphisms and susceptibility to prostate cancer: A systematic review. Indian J Cancer 2016;53:213-5
| » Introduction|| |
Globally, prostate cancer (PC) is the fourth most common cancer among men. PC incidence is the highest among black American in the United States; however, low incidence has been reported in Asian countries such as China, Japan, and India. Development of PC has been a versatile phenomenon and numerous factors such as age, race, dietary and lifestyle, environmental, and genetic causes have been attributed. Previous studies have shown that consumption of red meat, cigarette smoking, and exposure of various carcinogens from industries play a significant role in PC susceptibility in different ethnicities.,,,,,
The enzymes of the cytochrome P450 (CYP450) family play an important role in the activation of exogenous and/or endogenous carcinogens to more reactive metabolites that may react with DNA and cause mutations; however, Phase II enzymes, such as the glutathione S-transferases (GSTs), and microsomal epoxide hydrolase (mEH) are generally involved in detoxification of chemical carcinogens by addition of conjugates in reactive metabolites.,, Recent studies have demonstrated that polymorphisms in mEH gene loci may be an important factor for genetic susceptibility of various cancers including the prostate.,, Although the underlying mechanisms related to PC and CYP450s as well as GSTs have been elucidated, but no comprehensive review in relation to mEH gene polymorphism and PC risk is available in the literature. Hence, in the present review, we have summarized the recent advances of mEH gene polymorphisms for the PC susceptibility.
| » Microsomal Epoxide Hydrolase|| |
mEH is a smooth endoplasmic reticulum enzyme, expressed in a large variety of cell types including the liver, prostate, and an epithelial cell which suggests that mEH may ensure widespread defense against potential genotoxic epoxides.,
Five classes of mammalian epoxide hydrolase have been characterized, which are immunologically and structurally distinct in nature. These are mEH; cytosolic hepoxilin A3 hydrolase; leukotriene A4 hydrolase; soluble epoxide hydrolase; and microsomal enzyme associated with a specific substrate such as cholesterol 5,6-oxide. The soluble form of epoxide hydrolase participates in metabolizing trans-substituted epoxides; however, other forms of epoxide hydrolase metabolize cis-configuration of epoxides.
mEH gene is also known as EPHX1, and present on the long arm of the chromosome 1 and 20 kb in size. It consists of eight introns and nine exons, of which exons 2–9 are the coding exons. Mammalian EPHX1 is a 51 kDa protein having 455 amino acid residues; attached to the cytosolic site of endoplasmic reticulum membrane by a single N-terminal anchor. Further, the anchor is connected to generic alpha/beta hydrolase fold by the 100 amino acid residues stretch.
mEH enzyme is a Phase II enzyme involved in oxidative defense against a number of environmental substances. In detoxification process, it metabolizes a broad array of epoxide substrates of cis-configuration of arenes, alkenes, and aliphatic epoxides from the polycyclic aromatic hydrocarbons (PAHs) and aryl amines, butadiene, and pesticides into the less-toxic trans-dihydrodiol through trans-addition of water. However, in some cases (benzo[a] pyrene present in tobacco smoke), highly reactive carcinogenic compounds (benzo[a] pyrene 7,8-diol-9,10 epoxide) are also generated., Thus, mEH plays an important role in both the metabolic activation and detoxification of environmentally exposed carcinogens.
Microsomal epoxide hydrolase gene polymorphisms
The mEH protein and nucleic acid sequences are highly conserved and appear universally expressed. Most commonly, two functional polymorphisms have been identified within exon 3 and 4 of the mEH gene, which results in His113Tyr and Arg139His amino acid substitutions, respectively.In vitro expression analyzes pointed that the corresponding mEH activities decrease approximately 40% due to a point mutation in exon 3; however, the amino acid substitution (Arg139His) induced by point mutation in exon 4 increases mEH activity by 25%., Beside the coding region, several other non-coding polymorphisms were also elucidated, which may possibly affect transcriptional regulation of the mEH gene.
| » Microsomal Epoxide Hydrolase Gene Polymorphisms and Prostate Cancer Risk|| |
Etiology of PC remains unclear because prostate carcinogenesis is a complex process involving both genetic as well as environmental factors.,,,,,, In environmental carcinogens metabolism, exposed carcinogens first require metabolic activation, evasion of detoxification, thereafter binding of activated carcinogens to DNA forming DNA adducts that are accountable for mutation during replication process and finally resulting into PC [Figure 1]. Previous data have shown that mEH enzyme plays a dual role due to its ability of both activation and detoxification of tobacco and other environmental carcinogens.,,,,,,, Consequently, increased activity of mEH may be responsible for cancer protection due to increased detoxification of exposed carcinogens in the body or enhances the risk due to activation of specific carcinogens. Globally, several studies have shown in literature relation to mEH gene polymorphisms (exon 3 and exon 4) and PC risk which is narrated in the following text.
|Figure 1: In normal process, exposed carcinogens may require metabolic activation by the Phase I enzymes (CYP450s) and forming less polar and more toxic activated intermediates. Phase I enzymes metabolized products now act as substrates for the Phase II enzymes which catalyzes the conjugation of glutathione, acetyl coenzyme, or epoxide hydroxyl group in activated carcinogens through the glutathione S-transferases, N-acetyltransferases, or microsomal ephoxide hydrolase and produce readily extractable less toxic, more polar hydrophilic compounds that may excreted out from the body through the bile or urine. However, in stress condition when exposed carcinogens are not metabolized properly may result more active intermediates and undergoes in evasion of detoxification. These active intermediates now bind to DNA, forming DNA adducts that are accountable for mutation during replication process and ultimately resulting into prostate cancer|
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Association between mEH gene polymorphism (exon 3) and PC was the first reported by the Figer et al. in Israeli Jewish population and has detected the significant higher frequency of His113 allele in Grade II tumor (18%) as compared to Grade I tumor (5.5%). A study from North India by Mittal and Srivastava has demonstrated a significant association with exon 3 His allele of the mEH gene (P < 0.001), whereas no association, could be established with exon 4 genotypes. Furthermore, in gene–environment interaction, we have observed significant associations between tobacco users with variant genotype of exon 3 (odds ratio [OR] = 4.9; P < 0.000) and His genotype for the exon 4 of mEH gene (P = 0.003). In contrast to our study, observation by Sivonova et al. in Slovak population has demonstrated a moderate association with the Arg genotypes of exon 4 for PC susceptibility alone or in combination with smoking habit; however, no association was observed with exon 3 of mEH gene.
Recently, a potential association between smoking and mEH gene polymorphism with PAH-DNA adducts levels revealed that Caucasian ever smokers had significantly higher PAH-DNA adducts levels than non-smokers in tumor cells. Furthermore, in combined effects between ethnicity, smoking, and mEH genotypes; authors observed significant interaction between ethnicity and in ever smoking, and ethnicity and mEH His139 genotypes (P = 0.02) in tumor cells of African-Americans as compared to Caucasians group.
Association between pesticides and mEH gene polymorphisms and susceptibility to PC was done by Koutros et al., in 2220 participants, has demonstrated significant association with polymorphisms in exon 3 and exon 4 of mEH gene and suggested that men carrying the variant allele for mEH gene have higher PC risk in high pesticides exposed group as compared to non-exposed group (OR = 2.1, P = 0.01). However, a multi-ethnic, population-based case–control study by Joshi et al. in American population have observed non-significant association either mEH gene polymorphisms alone or in combination with nutrient density-adjusted intake of red meat and poultry for PC risk.
Recently, a study by Catsburg et al. in 497 localized and 936 advanced PC cases and 760 controls have shown significant increased risk for localized PC with His/His genotypes of exon 3 of mEH gene (OR = 1.91) as compared to controls. Thus, the positive association between the His allele and localized PC may suggest that the slow allele may contribute toward increased metabolic activation, possibly by reducing the bioavailability of substrates for PAH epoxide detoxification.
| » Conclusion and Future Prospective|| |
mEH is a Phase II polymorphic gene encoding enzyme that metabolizes environmental and tobacco carcinogen. The epoxide hydrolase acts coordinately with CYP450s to inactivate the deleterious polycyclic hydrocarbon oxides and epoxides. Thus, epoxide hydrolase plays very important role in carcinogens biotransformation.,,,
As of now, only seven studies are available in the literature exploring the mEH gene polymorphism, gene-gene, and gene–environmental interaction in relation to PC risk. Of seven, five studies have shown significant association with mEH genotypes for PC risk.,,,, while in two studies no association could be established., In summary, these findings indicate that mEH exon 3 variant allele has a significant association in some ethnic group, whereas exon 4 in other ethnic population. However, among individuals who were exposed to tobacco/pesticide carcinogens, exon 3 variant genotypes, and wild type of exon 4 genotypes appear to have a greater impact on risk in comparison to non exposed group for the susceptibility of PC in the majority of the population. Additional genetic variants, possibly in regulatory regions of the mEH gene may also play an important role and may have both protective or promotional effect on PC susceptibility and warrants for future investigation. To evaluate the association between the gene-gene and gene–environmental interaction, adequate large sample size is needed. Nevertheless, the limited sample size was employed for exploring the combined effect of the two genotypes in many studies, which underscores the need for further large epidemiological studies to investigate these associations.
Dr. Daya Shankar Lal Srivastava conceived and designed the article, wrote, drafted, and edited the manuscript. The author is highly thankful to Pt. B. D. Sharma University of Health Science, Rohtak, for scientific encouragement and required support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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