|Year : 2015 | Volume
| Issue : 2 | Page : 239-241
Multidrug resistance 1 gene polymorphism in amlodipine-induced gingival enlargement
Kumaraswamy Naik Lambani Rama Naik1, Kapil Jhajharia2, Roopam Chaudhary1, Aravind Tatikonda3, Aprinderpal Singh Dhaliwal4, Rose Kanwaljeet Kaur5
1 Department of Oral and Maxillofacial Pathology, Surendera Dental College and Research Institute, Sri Ganganagar, Rajasthan, India
2 Faculty of Dentistry, Department of Conservative Dentistry and Endodontics, Melaka Manipal Medical College, Melaka, Malaysia
3 Department of Periodontics, Rama Dental College, Kanpur, Uttar Pradesh, India
4 Adesh Institute of Dental Sciences and Research, Bathinda, Punjab, India
5 Department of Periodontology and Oral Implantology, Dasmesh Institute of Research and Dental Sciences, Faridkot, Punjab, India
|Date of Submission||14-May-2014|
|Date of Acceptance||13-Oct-2014|
|Date of Web Publication||23-Apr-2015|
Dr. Kumaraswamy Naik Lambani Rama Naik
Department of Oral and Maxillofacial Pathology, Surendera Dental College and Research Institute, Sri Ganganagar, Rajasthan
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Gingival enlargement comprises any clinical condition in which an increase in the size of the gingiva is observed. It is a side effect associated with some distinct classes of drugs, such as anticonvulsants, immunosuppressant, and calcium channel blockers. Among calcium channel blockers, nifedipine causes gingival enlargement in about 10% of patients, whereas the incidence of amlodipine, a third-generation calcium channel blocker, induced gingival enlargement is very limited. Because the calcium antagonists, albeit to a variable degree, act as inhibitors of P-glycoprotein (P-gp), the gene product of multidrug resistance 1 (MDR1), and inflammation may modify P-gp expression. We hereby, report a case of amlodipine-induced gingival enlargement with MDR1 3435C/T polymorphism, associated with inflammatory changes due to plaque accumulation, in a 50-year-old hypertensive male patient. The genotype obtained for the polymorphism was a heteromutant genotype, thus supporting the contention that the MDR1 polymorphism may alter the inflammatory response to the drug.
Keywords: Amlodipine, gene polymorphism, gingival overgrowth
|How to cite this article:|
Naik KR, Jhajharia K, Chaudhary R, Tatikonda A, Dhaliwal AS, Kaur RK. Multidrug resistance 1 gene polymorphism in amlodipine-induced gingival enlargement. J Indian Soc Periodontol 2015;19:239-41
|How to cite this URL:|
Naik KR, Jhajharia K, Chaudhary R, Tatikonda A, Dhaliwal AS, Kaur RK. Multidrug resistance 1 gene polymorphism in amlodipine-induced gingival enlargement. J Indian Soc Periodontol [serial online] 2015 [cited 2021 Sep 17];19:239-41. Available from: https://www.jisponline.com/text.asp?2015/19/2/239/145837
| Introduction|| |
Medication-related gingival overgrowth has now metamorphosized as drug-induced gingival enlargement. Drugs associated with gingival enlargement can be broadly categorized into: Anticonvulsants, antihypertensive calcium channel blockers, and immunosuppressants. , The pathogenesis of drug-induced gingival enlargement is uncertain, and there appears to be no unifying hypothesis that links together the three commonly implicated drugs. , As a matter of fact, the pharmacologic effect of each of these drugs varies but all of them seem to act in a similar fashion on secondary target tissue, that is, the gingival connective tissue, causing common clinical histopathological findings. , Furthermore, this condition occurs exclusively in the gingival tissues associated with teeth and is not seen in edentulous areas, thus lending support to the contention that local factors like plaque work synergistically with the offending drug in inducing drug-induced gingival enlargement.
Amlodipine which is used to control hypertension and angina occasionally associated with gingival enlargement. , As the calcium antagonists act as inhibitors of P-glycoprotein (P-gp) to a variable degree, the genetic product of multidrug resistance 1 (MDR1) and inflammation may modify the P-gp expression.  Pharmacogenomics and pharmacogenetics studies have revealed that genetic polymorphisms of MDR1 are associated with alteration in P-gp expression and function. Further, 50 single nucleotide polymorphisms (SNPs) and 3 insertion/deletion polymorphisms have been found in the MDR1 gene and some of them, such as C3435T, have been identified to be a risk factor for drug-induced gingival enlargement.  The present paper reports a case of amlodipine-induced gingival enlargement with a detailed analysis for MDR1 gene polymorphism.
| Case Report|| |
A 50-year-old male patient reported with a chief complaint of swollen and bleeding gums to the Department of Oral and Maxillofacial Pathology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Chandigarh. The patient was hypertensive for 2 years, and he was under treatment with amlodipine (05 mg/day, single dose orally). Intraoral examination revealed a firm, resilient, pale pink generalized gingival enlargement involving the attached, interdental and marginal gingiva of the maxillary and mandibular teeth [Figure 1]. Local irritating factors like plaque were present surrounding the dentition. On probing, periodontal pockets were obvious (2.5 ± 1.3 mm). Bleeding on probing was detected which was in accordance with mild superimposed gingival inflammation. Based on clinical examination and drug history, a provisional diagnosis of combined gingival enlargement was made. Routine blood investigations were within normal limits. The histopathological examination of the incisional biopsy specimen revealed hyperplastic keratinized stratified squamous epithelium with elongated rete ridges [Figure 2]. The underlying connective tissue component exhibited evidence of hyperplasia with sparse inflammatory cells subepithelially.
|Figure 1: Diffuse gingival enlargement seen with respect to maxillary and mandibular gingiva|
Click here to view
|Figure 2: Photomicrograph revealing hyperplastic stratified squamous epithelium with elongated rete ridges and fibrotic connective tissue with inflammation (H and E, ×10)|
Click here to view
Based on history, clinical and histopathological findings, the present case was suspected as a combined type of gingival enlargement; a drug-induced one (amlodipine), associated with inflammatory changes. Oral prophylaxis was done, and oral hygiene instructions were given. Review after 1-week revealed resolution of gingival enlargement to some extent. At the following visit, gingivectomy was performed for the unwanted enlarged gingiva. Patient was prescribed mouthwash chlorhexidine gluconate 0.12% for 2 weeks. Patient was recalled after 3 months, which revealed no evidence of recurrence.
Since the gingival enlargement in the present case was associated with amlodipine, this prompted us to go in for appropriate pharmacogenetic studies. Written consent was obtained from the patient. 5 ml of the blood sample was collected from subject's antecubital vein under aseptic conditions in a polypropylene tube containing 100 μl of anticoagulant - 10% ethylene diamine tetraacetic acid. Genomic DNA was extracted using Phenol-chloroform method, diluted to 50 ng/μl concentration and stored at −20°C. The sample was genotyped for MDR1 3435C>T using custom TaqMan genotyping assay on a real-time thermocycler by allelic discrimination method (Bio-Rd TouchTM Thermocycler, California) and the same methodology was validated by performing direct gene sequencing. The genotype obtained for the polymorphism was a heteromutant (CT) genotype.
| Discussion|| |
Amlodipine is a 3 rd generation dihydropyridine calcium antagonist that is used in the management of both hypertension and angina.  Jorgensen MG detected only mild hyperplasia and concluded that amlodipine did not induce gingival hyperplasia.  Ellis et al. first reported gingival sequestration of amlodipine and amlodipine-induced gingival overgrowth. , The mechanisms that trigger drug-induced gingival enlargement have not been completely understood, and although literature data are extensive, they are quite contradictory.  Some studies demonstrated that drugs associated with gingival enlargement are able to inhibit the production of extracellular matrix by gingival fibroblast and cell proliferation in vitro. , In contrast, others showed that the accumulation of proteins in extracellular matrix, particularly collagen, may occur due to an imbalance between the synthesis and the degradation of extracellular matrix, being the possible cause of the gingival enlargement. , Gingival enlargement has been proposed to have a multifactorial etiology involving an interaction of several factors. The major factors implicated in its etiology include drug metabolite interaction with the gingival fibroblasts, age, genetic predisposition, pharmacokinetic variables, drug-induced alterations in gingival connective tissue homeostasis and inflammatory changes. 
As a matter of fact, not all patients taking amlodipine develop gingival enlargement. Evidence suggests that genetic factors also might have a significant role in the pathogenesis of gingival enlargement and the patient's susceptibility to this unwanted effect. , A genetic predisposition could inﬂuence a variety of factors in the drug plaque-induced inﬂammation. These include gingival ﬁbroblast functional heterogeneity, collagenolytic activity, drug metabolism, and collagen synthesis. It has been speculated that drug-induced gingival enlargement may occur due to differences in the cell cycle and metabolism of fibroblasts, including collagen synthesis and breakdown between responders and nonresponders resulting in individual's susceptibility to those drugs. It has also been shown that the functional heterogenicity exists in gingival fibroblasts in response to various stimuli. ,
Inflammatory mechanism of drug-induced gingival enlargement includes the up-regulation of several growth factors and inﬂammatory cytokines such as interleukin-6 (IL-6), IL-1, IL-8, platelet-derived growth factor-β and transforming growth factor-β A synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts is found when these cells are exposed simultaneously to calcium channel blockers and elevated levels of interleukin-1β (a proinflammatory cytokine) in inflamed gingival tissues.  Furthermore, reduction of matrix metalloproteinases and augmentation of tissue inhibitors of matrix metalloproteinases is believed to inﬂuence the gingival enlargement development. Moreover, modulation of apoptosis could contribute to fibrosis in gingival tissues. It has been demonstrated that ﬁodulatio apoptosis is decreased in gingival enlargement and that this decrease may contribute to ﬁbrosis. 
It also needs to be emphasized that as the calcium antagonists act as inhibitors of P-gp to a variable degree, the genetic product of MDR1 and inflammation may modify the P-gp expression, which is expressed in the endothelial layers of blood vessels obtained from healthy or inflamed gingiva. It is also found that deeper gingival pockets/pseudopockets existed in subjects treated with calcium antagonists (amlodipine) as compared to drug-free counterparts. It has been found that this drug-related side effect is associated with the MDR1 3435C/T gene polymorphism. 
| Conclusion|| |
The present case is an example of a drug-induced (amlodipine) gingival enlargement that might be associated with MDR1 3435C/T polymorphism, as well as inflammatory changes due to plaque accumulation. The MDR1 polymorphism may alter the inflammatory response to the drug. The definitive treatment to such cases being drug substitution which seems to be the easiest and safest norm, but having said that science today has advanced leaps and bounds and it is possible in today's day and age to determine individual SNP profiles to identify the differences in our DNA.
| References|| |
Joshi S, Bansal S. A rare case report of amlodipine-induced gingival enlargement and review of its pathogenesis. Case Rep Dent 2013;2013:138248.
Joshipura V. Sodium valproate induced gingival enlargement with pre-existing chronic periodontitis. J Indian Soc Periodontol 2012;16:278-81.
Charles N, Ramesh V, Babu KS, Premalatha B. Gene polymorphism in amlodipine induced gingival hyperplasia: A case report. J Young Pharm 2012;4:287-9.
Li YH, Wang YH, Li Y, Yang L. MDR1 gene polymorphisms and clinical relevance. Yi Chuan Xue Bao 2006;33:93-104.
Jorgensen MG. Prevalence of amlodipine-related gingival hyperplasia. J Periodontol 1997;68:676-8.
Ellis JS, Seymour RA, Steele JG, Robertson P, Butler TJ, Thomason JM. Prevalence of gingival overgrowth induced by calcium channel blockers: A community-based study. J Periodontol 1999;70:63-7.
Corrêa JD, Queiroz-Junior CM, Costa JE, Teixeira AL, Silva TA. Phenytoin-induced gingival overgrowth: A review of the molecular, immune, and inflammatory features. ISRN Dent 2011;2011:497850.
Modéer T, Brunius G, Iinuma M, Lerner UH. Phenytoin potentiates interleukin-1-induced prostaglandin biosynthesis in human gingival fibroblasts. Br J Pharmacol 1992;106:574-8.
Spolidorio LC, Gonzaga HF, Spolidorio DM. Quantitative analysis of gingival tissues of rats treated with phenytoin and cyclosporine. Pesqui Odontol Bras 2000;14:327-33.
Babu SP, Ramesh V, Samidorai A, Charles NS. Cytochrome P450 2C9 gene polymorphism in phenytoin induced gingival enlargement: A case report. J Pharm Bioallied Sci 2013;5:237-9.
Hassell TM, Hefti AF. Drug-induced gingival overgrowth: Old problem, new problem. Crit Rev Oral Biol Med 1991;2:103-37.
[Figure 1], [Figure 2]