{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T16:58:22Z","timestamp":1790355502598,"version":"4.1.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2014,12,1]],"date-time":"2014-12-01T00:00:00Z","timestamp":1417392000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Haemonchus contortus<\/jats:named-content>larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH)<jats:italic>S<\/jats:italic>-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC<jats:sub>50<\/jats:sub>) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">H. contortus<\/jats:named-content>larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field.<\/jats:p>","DOI":"10.1128\/aac.03333-14","type":"journal-article","created":{"date-parts":[[2014,10,7]],"date-time":"2014-10-07T07:44:04Z","timestamp":1412667844000},"page":"7475-7483","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae"],"prefix":"10.1128","volume":"58","author":[{"given":"Andrew C.","family":"Kotze","sequence":"first","affiliation":[{"name":"CSIRO Agriculture Flagship, St. Lucia, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela P.","family":"Ruffell","sequence":"additional","affiliation":[{"name":"CSIRO Agriculture Flagship, St. Lucia, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron B.","family":"Ingham","sequence":"additional","affiliation":[{"name":"CSIRO Agriculture Flagship, St. Lucia, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2004.08.001"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2010.11.008"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1071\/EA02229"},{"key":"e_1_3_1_5_2","first-page":"75","volume-title":"The epidemiology and control of gastrointestinal parasites of sheep in Australia","author":"Prichard RK","year":"1978","unstructured":"PrichardRK. 1978. Sheep anthelmintics, p 75\u2013107. In DonaldADSouthcottWHDineenJK (ed), The epidemiology and control of gastrointestinal parasites of sheep in Australia. Academic Press, Sydney, Australia."},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-0813.1981.tb00451.x"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetpar.2004.10.019"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetpar.2011.11.060"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-011-2407-3"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-011-2410-8"},{"key":"e_1_3_1_11_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/978-1-4684-4466-7_9","volume-title":"Pest resistance to pesticides","author":"Dauterman WC","year":"1983","unstructured":"DautermanWC. 1983. Role of hydrolases and glutathione S-transferases in insecticide resistance, p 229\u2013247. In GeorghiouGPSaitoT (ed), Pest resistance to pesticides. Plenum Press, New York, NY."},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.24.040184.000315"},{"key":"e_1_3_1_13_2","first-page":"731","volume-title":"Comprehensive insect physiology, biochemistry and pharmacology","author":"Oppenoorth FJ","year":"1985","unstructured":"OppenoorthFJ. 1985. Biochemistry and genetics of insecticide resistance, p 731\u2013770. In KerkutGAGilbertLJ (ed), Comprehensive insect physiology, biochemistry and pharmacology, vol. 12. Insect control. Pergamon, New York, NY."},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0965-1748(99)00038-7"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(69)90041-6"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0048-3575(73)90098-9"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0048-3575(82)90015-3"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-6055.1995.tb01319.x"},{"key":"e_1_3_1_19_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/jee\/90.1.15","article-title":"Diflubenzuron tolerance associated with monooxygenase activity in field strain larvae of the Australian sheep blowfly (Diptera:Calliphoridae)","volume":"90","author":"Kotze AC","year":"1997","unstructured":"KotzeACSalesNBarchiaIM. 1997. Diflubenzuron tolerance associated with monooxygenase activity in field strain larvae of the Australian sheep blowfly (Diptera:Calliphoridae). J. Econ. Entomol. 90:15\u201320.","journal-title":"J. Econ. Entomol."},{"issue":"2","key":"e_1_3_1_20_2","doi-asserted-by":"crossref","first-page":"43S","DOI":"10.1016\/S0031-6997(25)06800-0","article-title":"Induction of cytochrome P450 by xenobiotics","volume":"36","author":"Bresnick E","year":"1984","unstructured":"BresnickEFoldesRHinesRN. 1984. Induction of cytochrome P450 by xenobiotics. Pharmacol. Rev. 36(2 Suppl):43S\u201351S.","journal-title":"Pharmacol. Rev."},{"key":"e_1_3_1_21_2","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1042\/bj2810577","article-title":"Phenobarbital induction of cytochrome P-450 gene expression","volume":"281","author":"Waxman DJ","year":"1992","unstructured":"WaxmanDJAzaroffL. 1992. Phenobarbital induction of cytochrome P-450 gene expression. Biochem. J. 281:577\u2013592.","journal-title":"Biochem. J."},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.en.29.010184.000443"},{"key":"e_1_3_1_23_2","first-page":"357","article-title":"The isoenzymes of glutathione transferase","volume":"57","author":"Mannervik B","year":"1985","unstructured":"MannervikB. 1985. The isoenzymes of glutathione transferase. Adv. Enzymol. 57:357\u2013417.","journal-title":"Adv. Enzymol."},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.3109\/00498259009046831"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0020-7519(96)00161-0"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0020-7519(84)90045-6"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-8-r88"},{"key":"e_1_3_1_28_2","first-page":"41","volume-title":"Piperonyl butoxide","author":"Hodgson E","year":"1998","unstructured":"HodgsonELeviPE. 1998. Interactions of piperonyl butoxide with cytochrome P450, p 41\u201354. In JonesDG (ed), Piperonyl butoxide. Academic Press, London, United Kingdom."},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1603\/029.102.0637"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(81)77010-1"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1603\/EC09122"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/0742-8413(95)02027-6"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.32.4.413"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.007369"},{"key":"e_1_3_1_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4017(88)90077-5"},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0020-7519(94)00087-5"},{"key":"e_1_3_1_37_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182009006386"},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0020-7519(99)00064-8"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_3_1_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-9861(71)80012-7"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/ps.996"},{"key":"e_1_3_1_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00931534"},{"key":"e_1_3_1_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004360100408"},{"key":"e_1_3_1_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetpar.2005.11.001"},{"key":"e_1_3_1_45_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182000061369"},{"key":"e_1_3_1_46_2","doi-asserted-by":"publisher","DOI":"10.1006\/expr.1994.1067"},{"key":"e_1_3_1_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4894(91)90081-7"},{"key":"e_1_3_1_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/jez.a.324"},{"key":"e_1_3_1_49_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20101346"},{"key":"e_1_3_1_50_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182012000595"},{"key":"e_1_3_1_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetpar.2013.03.018"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.03333-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.03333-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T01:24:49Z","timestamp":1746408289000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.03333-14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2014,12]]}},"alternative-id":["10.1128\/AAC.03333-14"],"URL":"https:\/\/doi.org\/10.1128\/aac.03333-14","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12]]},"assertion":[{"value":"2014-05-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-09-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-11-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}