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      • Record: found
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      Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study

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          Abstract

          Background

          The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness.

          The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use.

          Methods

          The following polymorphisms were analyzed; a synonymous MDR1 C3435T (rs1045642) in exon26, G-rs3789243-A in intron3, the functional BCRP C421A (rs2231142), the two COX-2 A-1195G (rs689466) and G-765C (rs20417) in the promoter region, and the COX-2 T8473C (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study.

          Results

          Carriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR) = 1.52, 95% Confidence Interval (CI): 1.12-2.06). Carriers of the variant allele of MDR1 C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR = 0.71 (CI:0.50-1.00)). There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous MDR1 C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16) whereas variant allele carriers were not at increased risk (p for interaction = 0.02). COX-2 and BCRP polymorphisms were not associated with CRC risk. There was interaction between NSAID use and MDR1 C3435T and COX-2 T8473C (p-values for interaction 0.001 and 0.04, respectively).

          Conclusion

          Two polymorphisms in MDR1 were associated with CRC risk and there was interaction between these polymorphisms and meat intake in relation to CRC risk. Our results suggest that MDR1 polymorphisms affect the relationship between meat and CRC risk.

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          Most cited references63

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          Biochemical, cellular, and pharmacological aspects of the multidrug transporter.

          S Ambudkar, S. Dey, C A Hrycyna … (1999)
          Considerable evidence has accumulated indicating that the multidrug transporter or P-glycoprotein plays a role in the development of simultaneous resistance to multiple cytotoxic drugs in cancer cells. In recent years, various approaches such as mutational analyses and biochemical and pharmacological characterization have yielded significant information about the relationship of structure and function of P-glycoprotein. However, there is still considerable controversy about the mechanism of action of this efflux pump and its function in normal cells. This review summarizes current research on the structure-function analysis of P-glycoprotein, its mechanism of action, and facts and speculations about its normal physiological role.
          Article 0 comments Cited 243 times – based on 0 reviews     Review now
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            Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense.

            Elaine Leslie, Roger G Deeley, Susan P C Cole (2005)
            In tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.
            Article 0 comments Cited 230 times – based on 0 reviews     Review now
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              Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.

              Enrico Flossmann, Peter M. Rothwell (2007)
              Randomised trials have shown that aspirin reduces the short-term risk of recurrent colorectal adenomas in patients with a history of adenomas or cancer, but large trials have shown no effect in primary prevention of colorectal cancer during 10 years' follow-up. However, the delay from the early development of adenoma to presentation with cancer is at least 10 years. We aimed to assess the longer-term effect of aspirin on the incidence of cancers. We studied the effect of aspirin in two large randomised trials with reliable post-trial follow-up for more than 20 years: the British Doctors Aspirin Trial (N=5139, two-thirds allocated 500 mg aspirin for 5 years, a third to open control) and UK-TIA Aspirin Trial (N=2449, two-thirds allocated 300 mg or 1200 mg aspirin for 1-7 years, a third placebo control). We also did a systematic review of all relevant observational studies to establish whether associations were consistent with the results of the randomised trials and, if so, what could be concluded about the likely effects of dose and regularity of aspirin use, other non-steroidal anti-inflammatory drugs (NSAID), and the effect of patient characteristics. In the randomised trials, allocation to aspirin reduced the incidence of colorectal cancer (pooled HR 0.74, 95% CI 0.56-0.97, p=0.02 overall; 0.63, 0.47-0.85, p=0.002 if allocated aspirin for 5 years or more). However, this effect was only seen after a latency of 10 years (years 0-9: 0.92, 0.56-1.49, p=0.73; years 10-19: 0.60, 0.42-0.87, p=0.007), was dependent on duration of scheduled trial treatment and compliance, and was greatest 10-14 years after randomisation in patients who had had scheduled trial treatment of 5 years or more (0.37, 0.20-0.70, p=0.002; 0.26, 0.12-0.56, p=0.0002, if compliant). No significant effect on incidence of non-colorectal cancers was recorded (1.01, 0.88-1.16, p=0.87). In 19 case-control studies (20 815 cases) and 11 cohort studies (1 136 110 individuals), regular use of aspirin or NSAID was consistently associated with a reduced risk of colorectal cancer, especially after use for 10 years or more, with no difference between aspirin and other NSAIDs, or in relation to age, sex, race, or family history, site or aggressiveness of cancer, or any reduction in apparent effect with use for 20 years or more. However, a consistent association was only seen with use of 300 mg or more of aspirin a day, with diminished and inconsistent results for lower or less frequent doses. Use of 300 mg or more of aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years, which is consistent with findings from observational studies. Long-term follow-up is required from other randomised trials to establish the effects of lower or less frequent doses of aspirin.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMC Cancer
                Title: BMC Cancer
                Publisher: BioMed Central
                ISSN (Electronic): 1471-2407
                Publication date Collection: 2009
                Publication date (Electronic): 21 November 2009
                Volume: 9
                Page: 407
                Affiliations
                [1 ]Medical Department, Viborg Regional Hospital, DK-8800 Viborg, Denmark
                [2 ]Clinical Biochemical Department, Viborg Regional Hospital, DK-8800 Viborg, Denmark
                [3 ]Danish Cancer Society, Institute of Cancer Epidemiology, DK-2100 Copenhagen, Denmark
                [4 ]Department of Clinical Epidemiology, Aarhus University Hospital, DK-9100 Aalborg, Denmark
                [5 ]National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark
                [6 ]National Food Institute, Technical University of Denmark, DK-2860 Søborg, Denmark
                Article
                Publisher ID: 1471-2407-9-407
                DOI: 10.1186/1471-2407-9-407
                PMC ID: 2797527
                PubMed ID: 19930591
                SO-VID: 5ad6531e-0616-4b1d-9eba-d3f5a81ee3c3
                Copyright © Copyright ©2009 Andersen et al; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 23 October 2008
                Date accepted : 21 November 2009
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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