<i>HLA-B*5901</i>
            is Strongly Associated with Methazolamide-Induced Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis

Kim, Sae‐Hoon; Kim, Myung‐Hwa; Lee, Kyung Wha; Kim, Sang‐Heon; Kang, Hye–Ryun; Park, Heung-Woo; Jee, Young Koo

doi:10.2217/pgs.10.54

Cited by 95 publications

(57 citation statements)

References 25 publications

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“…These include HLA-B*13:01 with dapsone [33], HLA-A*31:01, and HLA-B*15:11 with CBZ [28,29,34,35], HLA-B*15:02 with phenytoin [23,36], HLA-B*57:01 with abacavir [37], HLA-B*38 with sulfamethoxazole or lamotrigine [32], HLA-B*73 with oxicam [32], and HLA-B*59:01 with methazolamide [38]. A summary of genetic relationships between various HLA allotypes and drug-mediated SCARs is shown in Table 1.…”

Section: Genetic Susceptibility To Scarsmentioning

confidence: 99%

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

Hung²,

Fan

et al. 2016

IJMS

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Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine.

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Section: Genetic Susceptibility To Scarsmentioning

confidence: 99%

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

Hung²,

Fan

et al. 2016

IJMS

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“…SJS/TEN is now considered to be an autoimmune disease and some studies showed the strong correlation with methazolamide–induced SJS/TEN and HLA-B59 serotype that is often seen in East Asians [9, 43-45]. On the other hand, P450 is reported to the major target of the patients of autoimmune hepatitis, some of which related with certain HLA serotypes [46].…”

Section: Discussionmentioning

confidence: 99%

The Metabolism of Methazolamide in Immortalized Human Keratinocytes, HaCaT Cells

Sasabe

Maeda

Kishida

et al. 2017

DML

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Objective: Drug therapy is occasionally accompanied by an idiosyncratic severe toxicity, which occurs very rarely, but can lead to patient mortality. Methazolamide, an anti-glaucomatous agent, could cause severe skin eruptions called Stevens-Johnson syndrome/toxic epidermal necrolyis (SJS/TEN). Its precise etiology is still uncertain. In this study, the metabolism of methazolamide was investigated in immortalized human keratinocytes to reveal the possible mechanism which causes SJS/TEN.Methods: The metabolism of methazolamide was studied using immortalized human keratinocytes, HaCaT cells. HPLC was used to isolate a metabolite from the culture medium. Mass spectrometry (LC-MS/MS) was employed for its characterization. Three typical chemical inducers were assessed for the inducibility of cytochrome P450, and methimazole was used as the inhibitor of flavin-containing monooxygenase (FMO).Results: A sulfonic acid, N-[3-methyl-5-sulfo-1,3,4-thiadiazol-2(3H)-ylidene]acetamide (MSO) was identified as the final metabolite. Dexamethasone and β-naphthoflavone behaved as an inducer of cytochrome P450 in the metabolism, but isoniazid did not. The effect of methimazole was not consistent. We did not detect any glucuronide nor any mercapturic acid (N-acetylcysteine conjugate).Conclusion: N-[3-methyl-5-sulfo-1,3,4-thiadiazol-2(3H)-ylidene]acetamide (MSO) is not considered to be a direct product of an enzymatic reaction, but rather an auto-oxidation product of N-[3-methyl-5-sulfe-1,3,4-thiadiazol-2(3H)-ylidene]acetamide, a chemically unstable sulfenic acid, which is produced by cytochrome P450 from the β-lyase product of cysteine conjugate of methazolamide. MSO is considered to be susceptible to glutathione and to return to glutathione conjugate of methazolamide, forming a futile cycle. A hypothetical scenario is presented as to the onset of the disease.

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“…There are cases where a specific immune response to a drug can Pharmacogenomics (2012) 13(11) [72] A*3101 Japanese, northern European, Korean [58][59][60][61] Oxcarbazepine Han Chinese [48,64,140] Sulfamethoxazole B*38 European [104] Methazolamide B*5901, Cw*0102 alleles and B*5901-Cw*0102-A*2402 haplotype Korean and Japanese [142] Sulphonamides A*29, B*12 and DR7 European [143] Oxicam B*73 European [104] A*2 and B*12 European [143] Caucasians [146] A*3101 Northern European, Japanese, Korean [58][59][60][61] A*11 and B*51 (weak) Japanese [58] Delayed rash (nonsystemic)…”

Section: Models For Drug-induced Hypersensitivity Reactionsmentioning

confidence: 99%

HLA and Pharmacogenetics of Drug Hypersensitivity

Pavlos

Mallal

Phillips³

2012

Pharmacogenomics

160

132

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Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the pharmacological action of the drug. Such adverse drug reactions are associated with considerable morbidity and include severe cutaneous adverse reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis and the drug hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome). Over the last decade there have been many associations between these syndromes and Class I and II HLA alleles of the MHC, which have enriched and driven our knowledge of their immunopathogenesis. Significant translation has also occurred in the case of HLA-B*5701 screening being used to exclude at risk patients from abacavir and prevent abacavir hypersensitivity. The ultimate translation of the knowledge of how drugs interact with HLA would be applicable to preclinical drug screening programs to improve the safety and cost-effectiveness of drug design and development.

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HLA-B5901* is Strongly Associated with Methazolamide-Induced Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis

Abstract: A strong association was observed between HLA-B5901 and methazolamide-induced SJS/TEN in Korean patients. HLA-B5901 may be a useful screening marker for predicting methazolamide-induced SJS/TEN in patients of Korean and Japanese ancestry.

Cited by 95 publications

References 25 publications

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

The Metabolism of Methazolamide in Immortalized Human Keratinocytes, HaCaT Cells

HLA and Pharmacogenetics of Drug Hypersensitivity

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HLA-B*5901 is Strongly Associated with Methazolamide-Induced Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis

Abstract: A strong association was observed between HLA-B*5901 and methazolamide-induced SJS/TEN in Korean patients. HLA-B*5901 may be a useful screening marker for predicting methazolamide-induced SJS/TEN in patients of Korean and Japanese ancestry.

Cited by 95 publications

References 25 publications

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

The Metabolism of Methazolamide in Immortalized Human Keratinocytes, HaCaT Cells

HLA and Pharmacogenetics of Drug Hypersensitivity

Contact Info

Product

Resources

About

HLA-B5901* is Strongly Associated with Methazolamide-Induced Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis

Abstract: A strong association was observed between HLA-B5901 and methazolamide-induced SJS/TEN in Korean patients. HLA-B5901 may be a useful screening marker for predicting methazolamide-induced SJS/TEN in patients of Korean and Japanese ancestry.