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EDITORIAL
Year : 2012  |  Volume : 58  |  Issue : 4  |  Page : 233-234

CYP2B6: Inching towards personalized medicine


Editor, Journal of Postgraduate Medicine, India

Date of Web Publication4-Jan-2013

Correspondence Address:
N J Gogtay
Editor, Journal of Postgraduate Medicine'Nostalgia', ‘Nostalgia’, Ground Floor, College Building, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.105436

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How to cite this article:
Gogtay N J. CYP2B6: Inching towards personalized medicine. J Postgrad Med 2012;58:233-4

How to cite this URL:
Gogtay N J. CYP2B6: Inching towards personalized medicine. J Postgrad Med [serial online] 2012 [cited 2020 Feb 19];58:233-4. Available from: http://www.jpgmonline.com/text.asp?2012/58/4/233/105436


Enzymes of the cytochrome (CYP) P450 superfamily are predominant drug-metabolizing enzymes and approximately 15 enzymes among families 1-4 are responsible for xenobiotic metabolism. [1] Among the various CYP450 enzymes, CYP2B6 has been largely neglected and ignored by researchers because of lack of selective substrate probes or inhibitors, as also lack of mRNA or protein expression in the early studies with human liver samples. [2],[3] However, several recent studies that have used model substrates such as bupropion and technological advances applied to these substrates and the development of homology models have helped understand the role of this enzyme greatly. [4] CYP2B6 makes for 3%-6% of the total hepatic CYP content, and today it is known to and play a major role in the biotransformation of several drugs. In addition, a potential prognostic role for the enzyme in prostate cancer [5] has also been delineated. Many genetic polymorphisms in the CYP2B6 gene have been reported, and these are thought to be responsible for interindividual and interethnic differences in responses to CYP2B6 substrate drugs. [6],[7]

The importance of CYP2B6 to drug metabolism lies primarily in its polymorphic nature and its numerous complex haplotypes. The extensive genetic polymorphism leads to distinct ethnic and racial frequencies. Approximately 100 single-nucleotide polymorphisms (SNPs) have been identified and 29 of these SNPs result in amino acid substitutions. [8] Polymorphism can affect both protein expression level and functionality, and thereby affects drug clearance and efficacy. Bupropion and efavirenz are almost exclusively metabolized by the enzyme. Thus, the application of pharmacogenomics for the interpretation of drug toxicity and individual drug susceptibility for both methadone maintenance treatment and management of adverse events with efavirenz becomes important.

In the present issue of the Journal of Postgraduate Medicine, Musa et al. have evaluated the genetic polymorphism of CYP2B6 in three ethnic groups - the Malays, Chinese, and Indians, as well as opiate-dependent individuals from methadone maintenance clinics. [9] This is the first study in South East population including Malay Indians. Although the study is not sufficiently powered to demonstrate ethnic differences among the three ethnic groups studied, it has shown a difference suggesting ethnic differences. A total of 10 SNPs were evaluated in 424 healthy unrelated normal participants and 110 unrelated patients who were opiate dependent. The authors have documented nine previously reported haplotypes and three novel combinations of SNPs. The CYP2B6*6 (516G to T and 785A>g) allele which results in reduced levels of protein expression and activity was found at a higher frequency in the Malays (25.4%) relative to the other ethnic groups and opiate-dependent individuals. While this could be a chance finding, it could have implications in view of the fact that heroin dependence is more common among Malays. Most antiretrovirals used in the management of HIV are metabolized by the CYP450 family of enzymes, as also drugs of abuse and methadone. Effective management of HIV requires adherence, which in turn requires successful treatment of opioid addiction. Given the dual epidemic of drug use disorder and HIV/AIDS in the country, the study by Musa et al. is important in that it adds to the growing body knowledge on CYP2B6 polymorphism worldwide and to Malaysia and South East Asia in particular.

In India, the distribution of genotype and allele frequency of CYP2B6 is not studied in detail. A few studies have investigated influence of the CYP2B6 polymorphism on the pharmacokinetics of efavirenz and nevirapine in HIV-infected patients in South India. The studies showed that genetic polymorphism of CYP2B6 influences the plasma level of HIV drugs. [10],[11],[12] Since CYP2B6 is involved in the metabolism of many other drugs, namely artemisinin, bupropion, cyclophosphamide, diazepam, ifosfamide, ketamine, meperidine, methadone, midazolam, nicotine, propofol, selegiline, and tamoxifen, its genetic polymorphism will have important clinical implications. Further studies are also needed to investigate the nuclear receptor mediated regulation of CYP2B6 expression, transcriptional regulation, and associated toxicity. Since the occurrence of both drug toxicity and efficacy tend to be multi-factorial, the eventual application of the knowledge of genetic polymorphisms to patient care will depend on the identification of maximum number of factors responsible and technology becoming cost-effective.

 
 :: References Top

1.Wang H, Tompkins LM. CYP2B6: New insights into a historically overlooked Cytochrome P450 isoenzyme. Curr Drug Metab 2008;9:598-610.  Back to cited text no. 1
    
2.Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994;270:414-23.  Back to cited text no. 2
    
3.Ekins S, Wrighton SA. The role of CYP2B6 in xenobiotic metabolism. Drug Metab Rev 1999;31:719-54.  Back to cited text no. 3
    
4.Ekins S, Iyer M, Krasowski MD, Kharasch ED. Molecular characterization of CYP2B6 substrates. Curr Drug Met 2008;9:363-73.  Back to cited text no. 4
    
5.Kumagai J, Fujimura T, Takahashi S, Urano T, Ogushi T, Horie-Inoue K, et al. Cytochrome P4502B6 is a growth inhibitory and prognostic factor for prostate cancer. Prostate 2007;67:1029-37.  Back to cited text no. 5
    
6.Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M. Polymorphic CYP2B6: Molecular mechanisms and emerging clinical significance. Pharmacogenomics 2007;8:743-59.  Back to cited text no. 6
    
7.Mo SL, Liu YH, Duan W, Wei MQ, Kanwar JR, Zhou SF. Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. Curr Drug Metab 2009;10:730-53.  Back to cited text no. 7
    
8.Available from: http://www.pharmgkb.org/gene [Last accessed on 2012 Dec 01].  Back to cited text no. 8
    
9.Musa N, Zulkafli MI, Talib N, Mohamad N, Fauzi H, Ismail R. Haplotype frequencies of CYP2B6 in Malaysia. J Postgrad Med 2012;58:233-9.  Back to cited text no. 9
    
10.Swaminathan S, Ramachandran G, Agibothu Kupparam HK, Mahalingam V, Soundararajan L, Perumal Kannabiran B, et al. Factors influencing plasma nevirapine levels: A study in HIV-infected children on generic antiretroviral treatment in India. J Antimicrob Chemother 2011;66:1354-9.   Back to cited text no. 10
    
11.Ramachandran G, Ramesh K, Hemanth Kumar AK, Jagan I, Vasantha M, Padmapriyadarsini C, et al. Association of high T allele frequency of CYP2B6 G516T polymorphism among ethnic south Indian HIV-infected patients with elevated plasma efavirenz and nevirapine. J Antimicrob Chemother 2009;63:841-3.   Back to cited text no. 11
    
12.Ramachandran G, Hemanth Kumar AK, Rajasekaran S, Kumar P, Ramesh K, Anitha S, et al. CYP2B6 G516T polymorphism but not rifampin coadministration influences steady-state pharmacokinetics of efavirenz in human immunodeficiency virus-infected patients in South India. Antimicrob Agents Chemother 2009;53:863-8.  Back to cited text no. 12
    




 

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