|Year : 2019 | Volume
| Issue : 1 | Page : 39-41
Effect of ATP-Binding cassette, Sub-Family B polymorphism on plasma nevirapine and efavirenz levels in human immunodeficiency virus with tuberculosis-infected cases: A molecular structure analysis
Pathum Sookaromdee1, Viroj Wiwanitkit2
1 TWS Medical Center, Bangkok, Thailand
2 Department of Biological Science, Josepeh Ayobabalola University, Ikeji-Arakeji, Osun State, Nigeria
|Date of Submission||20-Nov-2018|
|Date of Decision||28-Jan-2019|
|Date of Acceptance||31-Jan-2019|
|Date of Web Publication||13-Mar-2019|
Dr. Pathum Sookaromdee
TWS Medical Center, Bangkok
Source of Support: None, Conflict of Interest: None
Background: Tuberculosis (TB) is an important infection that is usually seen in the patient with underlying human immunodeficiency virus (HIV) infection. An important concern on the cases with HIV/TB is the management of HIV by antiretroviral drug treatment (antiretroviral therapy). The effect of underlying genetic factor is interesting. The effect of adenosine triphosphate-binding cassette, sub-family B (ABCB-1) polymorphism on plasma nevirapine and efavirenz levels is inconclusive. Methods: The authors perform standard molecular structure analysis to assess the effect of C and T alleles of ABCB-1 C3435T polymorphism. The phenotype expressions, reflected by nevirapine and efavirenz levels, are comparatively studied. Results: With focus on 3435 position, the ratio of derived molecular weight after quantum assessment, comparing CC to CT and TT genotypes, is equal to 1:1.068:1.135. Conclusion: The authors can identify the effect of ABCB-1 on the plasma nevirapine and efavirenz levels in HIV/TB patients.
Keywords: Adenosine triphosphate-binding cassette, efavirenz level, human immunodeficiency virus, nevirapine, polymorphism, sub-family B, tuberculosis
|How to cite this article:|
Sookaromdee P, Wiwanitkit V. Effect of ATP-Binding cassette, Sub-Family B polymorphism on plasma nevirapine and efavirenz levels in human immunodeficiency virus with tuberculosis-infected cases: A molecular structure analysis. Biomed Biotechnol Res J 2019;3:39-41
|How to cite this URL:|
Sookaromdee P, Wiwanitkit V. Effect of ATP-Binding cassette, Sub-Family B polymorphism on plasma nevirapine and efavirenz levels in human immunodeficiency virus with tuberculosis-infected cases: A molecular structure analysis. Biomed Biotechnol Res J [serial online] 2019 [cited 2019 Mar 25];3:39-41. Available from: http://www.bmbtrj.org/text.asp?2019/3/1/39/254101
| Introduction|| |
Tuberculosis (TB) is an important infection that can cause the pulmonary and extrapulmonary manifestations. This infection is a common problem in the patient with underlying human immunodeficiency virus (HIV) infection. An important concern on the cases with HIV/TB is the management of HIV by antiretroviral drug treatment (antiretroviral therapy [ART]) combining with antituberculosis drug treatment., The effect of an underlying genetic factor is usually referred to.
Of several genetic polymorphisms, the effect of adenosine triphosphate-binding cassette, sub-family B (ABCB-1) polymorphism on plasma nevirapine and efavirenz levels is interesting but inconclusive. According to the study Uttayamakul et al., the plasma nevirapine and efavirenz levels were not affected by ABCB-1 genetic polymorphisms. All cases in the study are new identified HIV infection, and there is no chance of reinfection. The frequencies of CC, CT, and TT genotypes in this previous report are equal to 34%, 45%, and 12%, respectively. In that study, Uttayamakul et al. identified the ABCB-1 C3435T polymorphisms via genotyping using real-time polymerase chain reaction (PCR) technique and found that all HIV-infected patients with CT genotype had HIV-1 RNA levels of <50 copies/ml, which were different from the findings in the HIV-infected cases with other genotypes (CC and TT). There is no difference of the genotype frequencies in the cases with good or poor response to antiretroviral drug. These results are similar to those reported by Mahungu et al. that there was no effect of ABCB-1 genetic polymorphisms on blood nevirapine levels. Nevertheless, Saitoh et al. found that ABCB-1 3435 C/T or T/T genotypes were associated with higher blood and cerebrospinal fluid levels of nevirapine in HIV-infected cases. However, an important consideration in those mentioned studies is the possible effect of other confounding genetic polymorphisms (such as hepatic cytochrome P450 isoform polymorphism) that might affect the focused antiretroviral drug levels. The study that can control the confounding effect is required for clarification of the phenomenon. The main aim of the present study is to perform a bioinformatic study that can control the mentioned confounding factor. Here, the authors perform a study to assess the effect of polymorphisms of ABCB-1 on the ABCB-1 levels in HIV/TB patients.
| Methods|| |
The authors perform standard molecular structure analysis using the standard molecular quantum calculation technique as used in the previous studies.,, The aim of the analysis is to assess the effect of C and T alleles of ABCB-1 C3435T polymorphism on the phenotype expressions, reflected by nevirapine and efavirenz levels. The phenotypic expressions are predicted and comparatively studied. This work is a bioinformatics study not dealing with the human, animal, or clinical specimens.
The standard biochemical structure of the ABCB-1 available in the PubMed database (www.pubmed.com) was directly used as primary templates. Furthermore, the molecular structures of the studied antiretroviral drugs, nevirapine and efavirenz, were also used for further studies. The standard protocols as used in the previous studies were used. The structure clarification of the ABCB-1 molecule was first computational reclarified by a standard biochemioinformatic tool, CATH, which is a referencing tool for structure-based functional annotations for genome sequences. Then, the simulation of the molecular change at the specific site, 3435, is done for all three corresponding studied variant genotypes, CC, TT, and CT. Further, the standard quantum chemical calculations were carried out using the density functional theory with atomistic simulation studies (COMPASS) molecular dynamic simulation according to the standard simulation protocol proposed by Nwankwo et al. This technique is a mathematical technique based on equation construction and calculating.
Regarding the simulation study on the effect of genotype variant, the expressional prediction is done. The simulation analysis in the present study is according to the standard predictive analysis used in referencing publications,,, a genetic code is directly used for a protein production and this results in a final phenotypic expression. All processes are computational analyzed. Neither in vivo nor in vitro PCR test is used. No informed consent is required. The work is ethically approved by the Local Ethical Committee of the Medical Center (Ethical approval number: TWS 12-2018, date April 6, 2018).
| Results|| |
According to the molecular structure analysis, with focus on 3435 position, the ratio of derived molecular weight after quantum assessment, comparing CC to CT and TT genotypes, is equal to 1:1.068:1.135. Based on further stimulation, one genetic variant molecule results in one final expression molecule, the least required energy for CC genotype, which implies the most final nevirapine and efavirenz levels, is observable.
| Discussion|| |
ABCB-1 plays cellular export of antiretroviral agents. Its effect on the biopharmacological process of ART in HIV/TB patients is an interesting issue that is widely studied. The association between ABCB-1 genetic polymorphisms and antiretroviral drug levels in HIV/TB patients is widely studied, and the results from different studies are different.,, The lack of association of ABCB-1 genetic polymorphism and the antiretroviral drug level observed in the previous study might be due to the lack of assessment of effect of interference from other genetic polymorphisms. Of interest, in the study with lack of association, however, the difference on virological response to the ART was observable. Only the study on the genetic polymorphism frequency pattern might not help clarify the exact molecular process that might explain the drug response.
In the present study, the authors use the standard molecular structure analysis and directly focus on the molecular weight change due to the interested focused site. The work is not an in vitro but in silico bioinformatics study. The authors did not study the gene frequency in susceptible and resistant patients, but the specific focus is on the degree of antiretroviral drug response. The HIV infection is the new infection, and it is no possibility for reinfection of HIV. The interference of other genetic polymorphisms can be controlled. According to the present assessment, there is an association. This association is the same way as seen on the previous report for the effect of the genetic polymorphism on blood clopidogrel concentration. In the previous report on the effect of ABCB-1 polymorphism and clopidogrel concentration by Joob and Wiwanitkit, the standard quantum calculation analysis showed a similar finding that the CC genotype contributes to the best favorable clopidogrel level. In the present study, the C allele seems to relate with more antiretroviral drug concentrations and can imply more effective virological response in HIV/TB cases. In fact, referring to the previous report by Uttayamakul et al., the virological response in CC and TT genotypes is equal to 95% and 67%, respectively. The present report can confirm the usefulness of pharmacogenetics study for explaining the drug response in HIV/TB cases and also help plan the proper case management strategies based on the advance biochemioinformatics technique.
| Conclusion|| |
According to the present study, there is an effect of ABCB-1 on the plasma nevirapine and efavirenz levels in HIV/TB patients. CC genotype contributes to more nevirapine and efavirenz levels. The investigation on ABCB-1 polymorphism might be useful in ART management of HIV/TB patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bruchfeld J, Correia-Neves M, Källenius G. Tuberculosis and HIV coinfection. Cold Spring Harb Perspect Med 2015;5:a017871.
Charbonnier F, Calmy A, Janssens JP. Tuberculosis and HIV co-infection: A therapeutic challenge. Rev Med Suisse 2011;7:2295-6, 2298-300.
Uttayamakul S, Likanonsakul S, Manosuthi W, Wichukchinda N, Shioda T, Khusmith S, et al.
Influence of ABCB-1 C3435T polymorphisms on plasma nevirapine and efavirenz levels and their effects on virologic and immunological outcomes in HIV/TB co-infected Thai adults under anti-retroviral therapy. Southeast Asian J Trop Med Public Health 2012;43:78-88.
Mahungu T, Smith C, Turner F, Egan D, Youle M, Johnson M, et al.
Cytochrome P450 2B6 516G-->T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population. HIV Med 2009;10:310-7.
Eloy P, Tessier A, Fan-Havard P, Chou M, Verstuyft C, Taburet AM, et al.
Genetics of nevirapine metabolic pathways at steady state in HIV-infected cambodians. Antimicrob Agents Chemother 2017;61. pii: e00733-17.
Saitoh A, Sarles E, Capparelli E, Aweeka F, Kovacs A, Burchett SK, et al.
CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children. AIDS 2007;21:2191-9.
Joob B, Wiwanitkit V. ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) polymorphism and clopidogrel concentration in acute coronary syndrome: Molecular change can explain the observed therapeutic concentration. Anatol J Cardiol 2016;16:303-4.
Joob B, Wiwanitkit V. Interleukin-2-330T/G and interleukin-10-1082A/G genetic polymorphisms and B-cell non-Hodgkin lymphoma Turk J Haematol 2018;35:301-2.
Sillitoe I, Dawson N, Lewis TE, Das S, Lees JG, Ashford P, et al.
CATH: Expanding the horizons of structure-based functional annotations for genome sequences. Nucleic Acids Res 2019;47:D280-4.
Nwankwo HU, Olasunkanmi LO, Ebenso EE. Experimental, quantum chemical and molecular dynamic simulations studies on the corrosion inhibition of mild steel by some carbazole derivatives. Sci Rep 2017;7:2436.
Srriwijitalai W, Wiwanitkit V. Interleukin-6 -174G/C polymorphism and end-stage renal disease: Is there any role? Saudi J Kidney Dis Transpl 2018;29:747-8.
] [Full text]
Michaud V, Bar-Magen T, Turgeon J, Flockhart D, Desta Z, Wainberg MA, et al.
The dual role of pharmacogenetics in HIV treatment: Mutations and polymorphisms regulating antiretroviral drug resistance and disposition. Pharmacol Rev 2012;64:803-33.