{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T19:14:48Z","timestamp":1777922088182,"version":"3.51.4"},"reference-count":50,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2017,10,31]],"date-time":"2017-10-31T00:00:00Z","timestamp":1509408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Lymphatic Research and Biology"],"published-print":{"date-parts":[[2017,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction:<\/jats:title>\n                    <jats:p>Benzopyrones are plant-derived chemicals which have an evidenced degree of clinical efficacy in lymphedema management indicated in past trials. Unfortunately, in some of these cases idiosyncratic hepatotoxicity have been documented in a minority of patients. This review aims to tackle the problem of benzopyrone (particularly coumarin) toxicity by considering their metabolic pathways and identifying relevant alleles needed to take a targeted pharmacogenetic approach in its future use.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>The nontoxic 7-hydroxylation and the toxic heterocyclic \u201cring-splitting\u201d epoxidation pathways are the two main detoxification pathways in the hepatometabolism of coumarin, the former catalyzed by CYP2A6 and the latter by possibly CYP1A and CYP2E. Acetaldehyde dehydrogenase (ALDH) clears toxic aldehyde intermediates. CYP2A6 polymorphism screening methods, including genotyping, by real-time polymerase chain reaction and chromatography\u2013mass spectroscopy functional metabolite assays; efficiency of these techniques are continually improving. ALDH polymorphisms have also been implicated, with clinically viable screening tests, rapid genotyping, and sensitive questionnaires already available for ALDH2*1\/ALDH2*2. Dysfunctional polymorphisms of the above genes and others are significantly more prevalent in Eastern Asian populations, uncommon in Caucasian populations. The role of other enzymes\/genes in the pathway is yet to be clarified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>Although screening techniques are becoming increasingly clinically feasible, uncertainty remains on the link between the genotype, metabolic phenotype, and the exact gene products involved. These must be elucidated further before a targeted pharmacogenomic approach is fully viable. In the meantime, treatment should be avoided in those with vulnerable familial and ethnic descents if used.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/lrb.2017.0020","type":"journal-article","created":{"date-parts":[[2017,10,31]],"date-time":"2017-10-31T16:48:42Z","timestamp":1509468522000},"page":"317-323","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":9,"title":["Strategies for Avoiding Benzopyrone Hepatotoxicity in Lymphedema Management\u2014The Role of Pharmacogenetics, Metabolic Enzyme Gene Identification, and Patient Selection"],"prefix":"10.1177","volume":"15","author":[{"given":"Minhao","family":"Hu","sequence":"first","affiliation":[{"name":"Flinders University","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil B.","family":"Piller","sequence":"additional","affiliation":[{"name":"Lymphoedema Clinical Research Unit","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2017,10,31]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-6915(99)00010-1"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01377124"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986708786242877"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2013.1132"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2009.7202"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2004.2.86"},{"key":"e_1_3_3_8_2","first-page":"269","volume-title":"High Protein Oedemas and the Benzo-Pyrones","author":"Casley-Smith JR","year":"1986","unstructured":"Casley-Smith JR, , Casley-Smith JR. High Protein Oedemas and the Benzo-Pyrones. JB Lippincott Company; 1986; pp. 269\u2013276."},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/000331970005100101"},{"key":"e_1_3_3_10_2","first-page":"1069","article-title":"Variation in acid and neutral protease activity in rats with thermal oedema together with the influence of various benzopyrones","volume":"23","author":"Piller NB","year":"1977","unstructured":"Piller NB. Variation in acid and neutral protease activity in rats with thermal oedema together with the influence of various benzopyrones. Arzn-Forsh (Drug Res), 1977; 23:1069\u20131073.","journal-title":"Arzn-Forsh (Drug Res)"},{"key":"e_1_3_3_11_2","first-page":"76","article-title":"Treatment of lymphedema by complex physical therapy with and without oral and topical benzopyrones: What should therapists and patients expect","volume":"29","author":"Casley-Smith JR","year":"1996","unstructured":"Casley-Smith JR, , Casley-Smith JR. Treatment of lymphedema by complex physical therapy with and without oral and topical benzopyrones: What should therapists and patients expect. Lymphology, 1996; 29:76\u201382.","journal-title":"Lymphology"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199902043400503"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0007-1226(88)90139-7"},{"key":"e_1_3_3_14_2","first-page":"31","article-title":"Benzo-pyrones in the treatment of lymphoedema","volume":"18","author":"Casley-Smith JR","year":"1999","unstructured":"Casley-Smith JR. Benzo-pyrones in the treatment of lymphoedema. Int Angiol, 1999; 18:31\u201341.","journal-title":"Int Angiol"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1251793"},{"key":"e_1_3_3_16_2","first-page":"1","article-title":"Australian adverse drug reactions","volume":"14","author":"Therapeutic Goods Administration","year":"1995","unstructured":"Therapeutic Goods Administration. Australian adverse drug reactions. Canberra, AU: Adverse Drug Reaction Advisory Committee, 1995; 14:1.","journal-title":"Canberra, AU: Adverse Drug Reaction Advisory Committee"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfh162"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.2217\/14622416.8.2.151"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.30.5.483"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2005.08.001"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2005.3.81"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(99)00200-0"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.tpj.6500348"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.15.156"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-6915(97)00066-5"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1081\/DMR-120023681"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-002-0480-3"},{"key":"e_1_3_3_28_2","first-page":"610","article-title":"Inter-individual variability of coumarin 7-hydroxylation (CYP2A6 activity) in an Iranian population","volume":"16","author":"Hassanzadeh Khayyat M","year":"2013","unstructured":"Hassanzadeh Khayyat M, , Vahdati Mashhadian N, , Eghbal S, , Jalali N. Inter-individual variability of coumarin 7-hydroxylation (CYP2A6 activity) in an Iranian population. Iran J Basic Med Sci, 2013; 16:610\u2013614.","journal-title":"Iran J Basic Med Sci"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00191161"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199210000-00005"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.5414\/CPP41141"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2008.05.001"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199204000-00002"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgw033"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2016.01.028"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/174050"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.35946\/arcr.v38.1.08"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010814-124915"},{"key":"e_1_3_3_39_2","first-page":"1107","article-title":"V. Determination of genotypes of human aldehyde dehydrogenase ALDH2 locus","volume":"35","author":"Yoshida A","year":"1983","unstructured":"Yoshida A, , Wang G, Dav\u00e9 V. Determination of genotypes of human aldehyde dehydrogenase ALDH2 locus. Am J Hum Genet, 1983; 35:1107\u20131116.","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_40_2","first-page":"8","article-title":"Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: Isozyme variation and its possible role in alcohol intoxication","volume":"32","author":"Harada S","year":"1980","unstructured":"Harada S, , Misawa S, , Agarwal DP, , Goedde HW. Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: Isozyme variation and its possible role in alcohol intoxication. Am J Hum Genet, 1980; 32:8\u201315.","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2012-0509"},{"key":"e_1_3_3_42_2","first-page":"1227","article-title":"Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men","volume":"12","author":"Yokoyama T","year":"2003","unstructured":"Yokoyama T, , Yokoyama A, , Kato H, et al. Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men. Cancer Epidemiol Biomarkers Prev, 2003; 12:1227.","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2016.08.041"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2016.12.015"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-6915(99)00046-0"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1080\/713688151"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-008-0595-2"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(97)00119-4"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1080\/10915810701583010"},{"key":"e_1_3_3_50_2","first-page":"29","article-title":"Treatment of secondary lymphedema of the upper limb with CYCLO 3 FORT","volume":"29","author":"Cluzan RV","year":"1996","unstructured":"Cluzan RV, , Alliot F, , Ghabboun S, , Pascot M. Treatment of secondary lymphedema of the upper limb with CYCLO 3 FORT. Lymphology, 1996; 29:29\u201335.","journal-title":"Lymphology"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1177\/000331979704800115"}],"container-title":["Lymphatic Research and Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/lrb.2017.0020","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/lrb.2017.0020","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/lrb.2017.0020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T20:10:52Z","timestamp":1777666252000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/lrb.2017.0020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,31]]},"references-count":50,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,12,1]]}},"alternative-id":["10.1089\/lrb.2017.0020"],"URL":"https:\/\/doi.org\/10.1089\/lrb.2017.0020","relation":{},"ISSN":["1539-6851","1557-8585"],"issn-type":[{"value":"1539-6851","type":"print"},{"value":"1557-8585","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,31]]}}}