Salivary Biomarkers and Their Application in the Diagnosis and Monitoring of the Most Common Oral Pathologies.

Saliva is a highly versatile biological fluid that is easy to gather in a non-invasive manner-and the results of its analysis complement clinical and histopathological findings in the diagnosis of multiple diseases. The objective of this review was to offer an update on the contribution of salivary biomarkers to the diagnosis and prognosis of diseases of the oral cavity, including oral lichen planus, periodontitis, Sjögren's syndrome, oral leukoplakia, peri-implantitis, and medication-related osteonecrosis of the jaw. Salivary biomarkers such as interleukins, growth factors, enzymes, and other biomolecules have proven useful in the diagnosis and follow-up of these diseases, facilitating the early evaluation of malignization risk and the monitoring of disease progression and response to treatment. However, further studies are required to identify new biomarkers and verify their reported role in the diagnosis and/or prognosis of oral diseases.

Elucidating the role of Cyclooxygenase-2 in the pathogenesis of oral lichen planus - an immunohistochemical study with supportive histochemical analysis.

OBJECTIVE: Oral lichen planus (OLP) is a chronic, inflammatory disorder that affects the oral mucous membrane. During an inflammatory response, several chemokines and cytokines are released by the cells of the immune system. Activation of MMPs, along with mast cell-derived chymase and tryptase, degrades the basement membrane structural proteins, resulting in basement membrane breaks. AIM: To investigate the association between the COX-2 expressions, presence of intact or degranulating mast cells within the connective tissue and the extent of basement membrane discontinuity in OLP cases. METHODS: This study included a total of 50 formalin-fixed paraffin-embedded specimens (FFPE) of histologically confirmed cases of idiopathic oral lichen planus. A retrospective cross-sectional analysis was carried out by immunohistochemistry to study the epithelial expression of COX-2 and by the use of special stains such as toluidine blue and periodic acid-Schiff (PAS) to study the mast cell count and basement membrane changes in the oral mucosal tissue, respectively. RESULTS: There was a significant (P = 0.03) association between the COX-2 expressions and mast cell count. As the intensity of COX-2 expression increased from mild to moderate or severe, the number of mast cell count almost doubled. CONCLUSION: Interaction between upregulation of COX-2, mast cell and basement membrane sets a vicious cycle which relates to the chronic nature of the disease. Inhibitors of COX-2 may reduce the inflammatory process preceding the immune dysregulation in OLP.

Evaluation of prolidase activity and oxidative stress in patients with oral lichen planus and oral lichenoid contact reactions.

OBJECTIVE: The aim of this study was to evaluate prolidase activity and oxidative stress in patients with oral lichen planus (OLP) and oral lichenoid contact reactions (OLCR) using serum and salivary samples and to compare these biomarkers with each other as well as with a group of healthy subjects in order to be able to opine their role in the estimation of OLP and OLCR. PATIENTS AND METHODS: Eighteen recently diagnosed patients with OLP, 32 patients with OLCR and 18 healthy controls with matched periodontal status were recruited to the study. Prolidase activity, lipid peroxidation product malondialdehyde (MDA), sialic acid (SA), and advanced oxidation protein products (AOPPs) levels in both serum and saliva were determined. Additionally, salivary flow rate and its buffering capacity were estimated. Statistical analyses were performed using the chi-square test, t-test, Mann-Whitney U-test, and Spearman's rho correlation coefficient. RESULTS: No statistically significant differences were observed between the study groups and the control group regarding to the basic characteristics and the periodontal status (P > 0.05). There were no statistically significant differences between OLP and OLCR groups regarding to the distribution of lesions' type, severity, and location (P > 0.05). No significant differences were found between the two study groups with regard to Prolidase activity, MDA, SA, and AOPPs (P ˃ 0.05), whereas statistically significant differences were found between the two study groups and the control group with regard to all evaluated parameters except of serum prolidase (P ˂ 0.01). Moderate correlation was found between salivary MDA and the OLP/OLCR lesion severity, whereas a weak correlation was observed between serum SA and the OLP/OLCR lesion severity (P ˂ 0.05). CONCLUSIONS: The findings of this study suggest an increased prolidase activity and oxidative stress and imbalance in the antioxidant defense system in biological fluids of patients with OLP and OLCR when compared with the healthy subjects. Both OLP and OLCR patients revealed almost similar prolidase activity and oxidative stress levels although these two conditions have different etiopathogenesis.

ALK1 expression in oral lichen planus: a possible relation to microvessel density.

OBJECTIVE: To assess the expression of activin receptor-like kinase 1 (ALK1) and investigate its possible relationship with microvessel density (MVD) in different forms of oral lichen planus (OLP) compared to controls' biopsies. METHODS: Biopsies from 20 reticular/papular OLP (R/PLP), 20 atrophic/erosive OLP (A/ELP) patients, and 20 healthy subjects were immunohistochemically analyzed and statistically compared and correlated for ALK1 expression and MVD as assessed by CD34 expression. RESULTS: All OLP specimens revealed the presence of positive cytoplasmic CD34 immunostaining in endothelial cells, with statistically high significant MVD in each of R/PLP (Median; M = 4.40) and A/ELP (M = 7.69) compared to controls (M = 1.16) (P < 0.001). Statistically significant MVD was found in A/ELP compared to R/PLP (P < 0.001). All control specimens revealed negative ALK1 immunostaining of the few inflammatory cells found, while 85% of A/ELP cases and 70% of R/PLP cases showed positively immunostained sections for ALK-1, with statistically significant higher ALK1 expression In A/ELP (M = 1.95) compared to R/PLP (M = 0.86) (P = 0.005). No significant correlation between CD34 and ALK1 was detected in R/PLP (r = 0.081), while a barely moderate positive correlation was found in A/ELP (r = 0.396). CONCLUSIONS: ALK1 expression and MVD are increased in OLP, particularly in A/ELP type.

Cathepsin K expression is increased in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is an idiopathic T-cell-mediated mucosal inflammatory disease. Cathepsin K (Cat K) is one of the lysosomal cysteine proteases. It is involved in many pathological conditions, including osteoporosis and cancer. The expression and role of Cat K in OLP are unknown. METHODS: Twenty-five oral mucosal specimens diagnosed histopathologically as OLP and fourteen healthy controls (HC) were used to study the immunohistochemical (IHC) expression of Cat K. Colocalization of Cat K with CD1a, Melan-A, CD68, CD45, mast cell tryptase (MCT), and Toll-like receptors (TLRs) 4 and 9 were studied using double IHC and/or immunofluorescence (IF) staining. Expression of Cat K was also evaluated in OLP tissue samples before and after topical tacrolimus treatment. RESULTS: Cat K was expressed in a higher percentage of cells in the epithelial zone, and the staining intensity was stronger in the stroma in OLP compared to controls (P < 0.001). In OLP, Cat K was present mostly in melanocytes and macrophages and sporadically in basal keratinocytes, endothelial cells, and extracellularly. Cat K was found also in some fibroblasts in HC and OLP samples. Coexpression of Cat K and TLRs 4 and 9 was seen in some dendritic cells (presumably melanocytes) and macrophages. In OLP, tacrolimus treatment reduced the expression of Cat K in the epithelium but increased it in the stroma. CONCLUSIONS: These results suggest that Cat K is involved in the pathogenesis of OLP. Cat K possibly takes part in the modulation of matrix molecules and cellular receptors.

[Expression and significance of p38 mitogen-activated protein kinase in oral lichen planus and oral squamous cell cacinoma].

OBJECTIVE: To assess the differences among the expressions of p38 mitogen activated protein kinases (MAPK), phospho-p38MAPK and nuclear factor kappa B (NF-κB) in oral lichen planus (OLP) and oral squamous cell carcinoma(OSCC). METHODS: In the study, 53 cases of OLP, 45 of OSCC, and 18 controls were obtained and 4-µm-thick histological sections were prepared from formalin-fixed paraffin-embedded tissue blocks.The expressions of p38MAPK,phospho-p38MAPK and NF-κB were detected by immunohistochemistry staining. Furthermore, the expressions of p38MAPK and phospho-p38MAPK were detected using Western blotting analyses in the fresh tissues from 11 cases of OLP, 5 cases of OSCC, and 7 cases of the controls. RESULTS: p38MAPK was over-expressed in the lamina propria, but lowly expressed in the epithelium in OLP group. Phospho-p38MAPK was lower expressed in OLP group than in OSCC and control groups.NF-κB was found over-expressed in the lamina propria in OLP group.p38MAPK was found expressed in all the samples in the 3 groups. The expression of phospho-p38MAPK was observed in 8 (8/11) OLP samples, 5 (5/5) OSCC samples and 4 (4/7) controls by Western blotting, but no significant differences were found within the 3 groups. CONCLUSION: p38MAPK can be detected in normal oral mucosa, OLP and OSCC. Phospho-p38MAPK may be related to the onset and progression of OSCC. The role of p38MAPK in OLP is yet to be revealed.

Altered expression of hyaluronan, HAS1-2, and HYAL1-2 in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is an immune-mediated mucosal disease of unclear etiology and of unresolved pathogenesis. Hyaluronan (HA) is an extracellular matrix glycosaminoglycan involved in inflammation and tumor progression. However, its presence in OLP has not been reported. We therefore aimed to study the immunohistochemical expression of HA, its receptor CD44, hyaluronan synthases (HAS1-3), and hyaluronidases (HYAL1-2) in OLP. METHODS: The presence of HA, CD44, HAS1-3, and HYAL1-2 was studied by immunohistochemical methods in 55 OLP and 23 control oral mucosal specimens (CTR). The localization, intensity, and differences of the epithelial expression between OLP and CTRs were analyzed. RESULTS: HA and CD44 were found on cell membranes in the epithelial basal and intermediate layers in CTR and OLP specimens. The HA staining intensity was stronger in the basal layer of the epithelium in OLP than in CTRs (P < 0.001). HAS1 (P = 0.001) and HAS2 (P < 0.001) showed stronger staining in the basal and weaker staining in the superficial (P < 0.001) epithelial layers in OLP than in CTRs. The immunostaining of HAS3 was low in both OLP and CTRs. Positive HYAL1 and HYAL2 staining were mainly found in the basal and intermediate epithelial layers, and their intensities were significantly increased in OLP, except HYAL 2 in the intermediate epithelial layer. CONCLUSIONS: HA, HAS1-2, and HYAL1-2 have altered expression in OLP compared to CTRs and may therefore have a role in OLP pathogenesis.

Interferon-γ regulates the function of mesenchymal stem cells from oral lichen planus via indoleamine 2,3-dioxygenase activity.

BACKGROUND: Little is known about mesenchymal stem cells (MSCs) in normal or inflammatory oral mucosal tissues, such as in oral lichen planus (OLP). Our objectives were to identify, isolate, and characterize MSCs from normal human oral mucosa and OLP lesions, and to evaluate indoleamine 2,3 dioxygenase (IDO) activity in mediating immunomodulation of MSCs from these tissues. METHODS: Expressions of MSCs-related markers were examined in isolated cells by flow cytometry. Self-renewal and multilineage differentiations were studied to characterize these MSCs. Interferon-γ (IFN-γ), IDO, and STRO-1 were assessed by immunofluorescence. MSCs from oral mucosa and OLP or IFN-γ-pretreated MSCs were co-cultured with allogeneic mixed lymphocyte reaction assays (MLR). Proliferation and apoptosis of MLR or MSCs were detected by CCK8 and the annexin V-FITC apoptosis detection kit, respectively. IDO expression and activity were measured by real-time PCR, Western blotting, and high-performance liquid chromatography. RESULTS: Isolated cells from oral mucosa and OLP expressed MSC-related markers STRO-1, CD105, and CD90 but were absent for hematopoietic stem cell markers CD34. Besides, they all showed self-renewal and multilineage differentiation capacities. MSCs in OLP presented STRO-1/IDO+ phenotype by immunofluorescence. MSCs and IFN-γ-pretreated MSCs could inhibit lymphocyte proliferation via IDO activity, but not via cell apoptosis. Long-term IFN-γ could also inhibit MSC proliferation via IDO activity. CONCLUSIONS: Mesenchymal stem cells can be isolated from human oral mucosa and OLP tissues. Besides self-renewal and multilineage differentiation properties, these cells may participate in immunomodulation mediated by IFN-γ via IDO activity in human OLP.

Serum and Saliva MMP-3 in Patients with OLP and Oral SCC.

BACKGROUND: Matrix metalloproteinase-3 (MMP-3) plays a key role in development of cancer. The purpose of this study was to assess MMP-3 in the serum and saliva of patients with oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Thirty patients with OLP (8 reticular and 22 erosive forms), and 20 patients with OSCC (6 in low stage and 14 in advanced stage), were enrolled in this study, conducted at the Cancer Department, Clinic of Oral Medicine, Tehran University of Medical Sciences. The serum and saliva MMP-3 was assayed by ELISA method. Statistical analysis of the Student's t-test, ANOVA and Pearson correlation coefficient was performed. The mean saliva and serum levels of MMP-3 were significantly higher in patients with OSCC compared with OLP. RESULTS: The serum and saliva MMP-3 concentrations increased from reticular form of OLP to erosive form of OLP, and increased further to low stage of OSCC and advanced stage of OSCC. Serum MMP-3 correlated significantly with unstimulated (r = 0.310, p = 0.038) and stimulated (r = 0.365, p < 0.026) saliva MMP-3. CONCLUSION: Serum and saliva MMP-3 levels appear associated with OLP and OSCC.

Nitric oxide synthase isoenzyme expression in human oral lichen planus.

The roles of nitric oxide (NO) synthase (NOS) enzyme in pathological mechanisms of the oral cavity are still incompletely understood. The aim of this study was to investigate the expression of the endothelial, neuronal and inducible isoforms of NOS (eNOS, nNOS and iNOS) in oral lichen planus (OLP) development in humans. OLP and healthy oral mucosa biopsies were taken for mRNA and protein analysis of NOS isoenzymes by RT-PCR, western blot and immunohistochemistry. The mRNA and protein levels of eNOS and nNOS were present in all samples, with a significant increase only for eNOS in OLP. The normal oral mucosa exhibited only small amounts of iNOS mRNA and protein, while it showed a significant rise in OLP samples. These results were confirmed by immunohistochemical analysis. Our findings suggest that NO produced by increased eNOS and iNOS expression may have circulatory and immune functions in the development of OLP.

Aldehyde dehydrogenase 1 expression correlated with malignant potential of oral lichen planus.

Oral lichen planus (OLP) is a potentially malignant disorder associated with an increased risk of oral squamous cell carcinoma (OSCC). The objective of this study was to determine protein expression of cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) in a series of patients with OLP and evaluate the correlation between ALDH1 expression and the risk of progression to OSCC. In a retrospective study, ALDH1 expression was determined using immunohistochemistry in samples from 101 patients with OLP who received a mean follow-up of 5 years, including 89 patients with untransformed OLP that did not develop into OSCC and 12 patients with malignant transformed OLP that had developed into OSCC. Analysis of 10 cases of normal oral mucosa and 6 cases of postmalignant OSCC form previously diagnosed OLP was also performed. The results showed that ALDH1 expression was observed in 27 (30.3%) of 89 cases of untransformed OLP and in 8 (66.7%) of 12 cases of transformed OLP (P = .021). Aldehyde dehydrogenase 1 was not expressed in normal oral mucosa, but it overexpressed in the 6 cases (100%) of OSCC. Multivariate analysis revealed that ALDH1 expression was significantly associated with a 6.71-fold (95% confidence interval, 1.64-27.42; P = .008) increased risk of malignant transformation. Collectively, ALDH1 expression was significantly associated with malignant transformation in a large series of patients with OLP. Our findings suggested that ALDH1 expression may identify a subgroup of a higher risk of malignant transformation of OLP.

The roles of matrix metalloproteinases-2, -7, -10 and tissue inhibitor of metalloproteinase-1 in the pathogenesis of oral lichen planus.

BACKGROUND: The aim of this study was to investigate the roles of Matrix Metalloproteinases (MMP)-2, Metalloproteinases-7, Metalloproteinases-10 and Tissue Inhibitors of Metalloproteinase-1 (TIMP-1) in the pathogenesis of oral lichen planus (OLP) disease in same tissue samples. METHODS: Thirty-nine individuals [29 patients with OLP (74%) and 10 healthy control subjects (25%)] were included in our study. The mean age was 48 ± 14.39 with a range of 20-75. RESULTS: MMP-2 and MMP-7 expression was significantly different in the patient and control groups in the epithelium and the connective tissue (P<0. 05). The ratio of MMP-2/TIMP-1 and MMP-7/TIMP-1 were higher in patient with OLP group than control group. CONCLUSIONS: Along with the exposure of the role of MMPs activity on diseases characterized by the tissue destruction, several studies were conducted on the pharmacological control of MMPs activity. However, understanding of the biological functions of MMPs is very important for the development and implementation of MMP inhibitors in the treatment of diseases. According to the results of this study, we suggest that MMP-2, MMP-7, and TIMP-1 may be involved in the formation of OLP lesions. Further studies on MMPs may be useful for understanding and treating the diseases such as OLP.

DNA polymorphisms and tissue cyclooxygenase-2 expression in oral lichen planus: a case-control study.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disorder defined as a precancerous condition. Special attention has been paid to the expression of cyclooxygenase-2 (COX-2) and its potential role in development of oral squamous cell carcinoma. The identification of single nucleotide polymorphisms that affect gene function or expression and contribute to disease predisposition has become a major area of investigation toward understanding the mechanisms for cancer. OBJECTIVE: The objective of this study is to investigate the association between the COX-2 765G>C gene polymorphism, tissue COX-2 expression and the development of OLP as a chronic inflammatory condition. METHODS: This study was done on 50 patients with OLP and 50 healthy controls. COX-2 activity was assessed by measuring tissue prostaglandin E (PGE)2 levels by enzyme immunometric assay kit. COX-2 765G>C gene polymorphism was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by restricted fragment length polymorphism (RFLP). RESULTS: OLP patients showed statistically significant higher mean PGE2 than the control group. We did not observe any statistically significant differences in genotype distribution or allele frequency between the patients and the control group (P > 0.05). Odds ratio showed no statistically significant association between COX-2 765G>C polymorphism and lichen planus. CONCLUSION: The present evidence thus indicates that variation in the COX-2 gene is unlikely to be of relevance to the aetiology of OLP. As this is the first report concerning the COX-2 -765G>C gene polymorphism and the risk of OLP, additional studies with larger sample size will be required to confirm these findings.

Increased levels of COX-2 in oral lichen planus supports an autoimmune cause of the disease.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease for which the pathogenesis is not fully understood. OLP has autoimmune features and auto immunity has been suggested as a potential cause, whereas WHO has classified OLP as a premalignant condition. Association between chronic inflammation and cancer is known and chronic inflammation is one of the characteristics of OLP. A protein connected to inflammation and suggested to be involved in cancer development is cyclooxygenase-2 (COX-2) which can be inhibited by microRNA-26b (miR-26b). OBJECTIVE: The aim was to map levels of COX-2 and miR-26b in OLP lesions to see if there was any correlation between expression of COX-2 and its regulator miR-26b in OLP. METHODS: In biopsies from 20 OLP patients and 20 age and gender-matched controls laser- micro dissection of epithelium was performed. Quantitative RT-PCR, immunohistochemistry and Western blot were used in the analysis. RESULTS: Levels of COX-2 mRNA were significantly higher while levels of miR-26b were significantly lower in OLP lesions compared to controls. Using immunohistochemistry normal oral mucosa samples did not show any expression of COX-2 while OLP samples expressed the protein. No COX-2 protein was detectable with Western blot. CONCLUSION: Increased expression of COX-2 and decreased expression of miR-26b in OLP suggests both to play a role in OLP. COX-2 has been connected to both malignant development and autoimmunity but as malignant development of OLP is quite rare we suggest that the increased levels of COX-2 seen here support an autoimmune cause of the disease.

Overexpression of cdk4 and p16 in oral lichen planus supports the concept of premalignancy.

BACKGROUND: Cell cycle arrest and increased cell proliferation have been demonstrated in oral lichen planus (OLP). This study evaluated the expression of cdk4, cdk6 and p16, important proteins in the G1 phase, in OLP and compared the expression of these proteins of OLP with those of normal mucosa. METHODS: Expression of cdk4, cdk6 and p16 were investigated in 23 OLP and 10 normal mucosae using immunohistochemistry technique. Positive cells were counted and presented as a percentage of positive cells. RESULTS: Expression of cdk4, cdk6 and p16 was observed in 3/10 (30%), 1/10 (10%) and none of normal mucosa, respectively. Expression of cdk4, cdk6 and p16 was detected in 18/23 (78.3%), 8/23 (34.8%) and 15/23 (65.2%), of OLP, respectively. The numbers of cdk4 and p16 positive cases of OLP were significantly higher than normal mucosa. In normal mucosa, the averages of the percentage of positive cells for cdk4 and cdk6 staining were 1.48 and 0.18, respectively. In OLP, the averages of the percentage of positive cells for cdk4, cdk6 and p16 staining were 2.73, 1.06 and 2.24, respectively. The percentage of cdk4-positive cells of OLP was significantly higher than those of normal mucosa group. CONCLUSION: Oral lichen planus demonstrated overexpression of cdk4 and p16, but not cdk6, suggesting that epithelial cells in OLP are in the hyperproliferative state and in cell arrest. Altered expression of cdk4 and p16 provides evidence of the malignant potential in OLP.

Can the genotype or phenotype of two polymorphic drug metabolising cytochrome P450-enzymes identify oral lichenoid drug eruptions?

BACKGROUND: Lichenoid drug eruptions (LDE) in the oral cavity are adverse drug reactions (ADR) that are impossible to differentiate from oral lichen planus (OLP) as no phenotypic criteria exist. Impaired function of polymorphic cytochrome 450-enzymes (CYPs) may cause increased plasma concentration of some drugs resulting in ADR/LDE. In an earlier study we did not find more patients with OLP (OLPs) with impaired CYP-genotype. OBJECTIVES: To test if more OLPs have an impaired CYP-phenotype than to be expected from the CYP-genotype and to find clinical criteria characterising oral LDE. METHODS: One hundred and twenty OLPs were genotyped for the most common polymorphisms of CYP2D6 and CYP2C19 that result in impaired function. One hundred and ten did a phenotype test of both enzymes. The exposure to drugs and polypharmacy and the CYP metabolism of the drugs were evaluated. The OLP manifestations were registered. RESULTS: The only difference in OLP manifestations was that patients with a CYP2D6 genotype with less than two fully functional alleles presented more asymmetrical OLP distribution in particular in non-medicated patients (P < 0.05). No more OLPs than expected from the genotype had a phenotype with reduced function. However, the established phenotypic categories could not differentiate between the genotypes with two or one fully functional allele. Nevertheless, among the patients with a phenotype with normal function the patients with only one functional allele had a statistically significant higher metabolic ratio compared to patients with two fully functional alleles (P < 0.05). CONCLUSION: It was not possible to identify LDE by impaired function of polymorphic CYPs.

Cytochrome P450 2D6 polymorphism and drug utilization in patients with oral lichen planus.

OBJECTIVE: Oral lichen planus (OLP) is one of the commonest diseases of the oral mucosa. The etiology of the disease is unknown. Our goal was to determine frequencies of functionally important alleles which determine the metabolic rate (phenotype) of individuals with OLP and to compare drug utilization, with focus on CYP2D6, with that of a control group. MATERIAL AND METHODS: The study population consisted of 46 patients with OLP, 60 sex- and age-matched control subjects for drug utilization evaluation and 223 healthy non-medicated controls for genotype comparison. DNA analysis was done using polymerase chain reaction and restriction fragment length polymorphism. The gene CYP2D6 was analyzed for the alleles CYP2D6*3,*4,*5,*6 and gene duplication. Drug utilization was evaluated according to Anatomical Therapeutic Chemical code, liver drug metabolism pathway and mono- or polytherapy. RESULTS: Intake of drugs was significantly higher in the group of OLP patients in comparison with control subjects. The use of CYP2D6 substrates, inhibitors or inducers did not differ between OLP patients and controls. Predicted phenotype frequencies in OLP patients and healthy controls, respectively were as follows: ultrarapid metabolizers 2% and 5.8%, extensive metabolizers 52% and 49.8%, intermediate metabolizers 39% and 37.7% and poor metabolizers 7% and 6.7%. CONCLUSIONS: We did not find a statistically significant difference in the frequency of CYP2D6 alleles between OLP patients and healthy controls. OLP patients used more medication than age- and sex-matched controls.

Polymorphic drug metabolizing CYP-enzymes--a pathogenic factor in oral lichen planus?

BACKGROUND: Oral lichen planus (OLP) is a chronic mucosal disease with a characteristic clinical phenotype. Environmental exposures, e.g. drugs have been associated with the pathogenesis. OBJECTIVES: To test the hypothesis that some OLP lesions have a pharmacological pathogenesis related to polymorphisms of the cytochrome P450 enzymes (CYPs) resulting in poor or intermediate CYP metabolism. METHODS: One hundred and twenty patients with OLP and 180 gender-matched controls without OLP were genotyped for CYP2C9, CYP2C19, and CYP2D6 alleles with absent or reduced function. RESULTS: The prevalence of poor or intermediate metabolizers was not higher among the OLPs as compared with the controls; however, there were higher numbers of variant CYP2D6 genotypes among the OLP females (P < 0.05). There were no differences between the groups with regard to intake of drugs metabolized by polymorphic CYPs or drug or herbal products inhibiting CYPs. The prevalence of CYP2D6*4 alleles among the OLPs was higher [28%; 95% confidence interval (CI) 20-36%] than previously reported among Danes (19%; 95% CI 17-22%). Fifty per cent of the OLPs had a CYP2D6*4 genotype as compared with 30% in the background population (P = 0.0001). The CYP2D6*4 protein has sequence homology with human herpes simplex virus type 1 (HSV1) and Candida albicans, which may result in molecular mimicry. CONCLUSION: It was not possible to substantiate a pharmacological pathogenesis of OLP based on poor or intermediate CYP metabolism. However, molecular mimicry between CYP2D6, in particular CYP2D6*4, and common oral pathogens may be involved in the pathogenesis of OLP.