{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:16:58Z","timestamp":1764688618777},"reference-count":36,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2006,7,14]],"date-time":"2006-07-14T00:00:00Z","timestamp":1152835200000},"content-version":"vor","delay-in-days":4577,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[1994,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In previous studies we have shown highly significant increases in chromosome damage and sister chromatid exchanges in heroin addicts, particularly when caffeine and metabolic inhibitors are added to the medium. Using human HUT\u201078 T\u2010cell cultures, we now find direct in vitro evidence of opiate\u2010induced or opiate\u2010promoted mutagenesis via several assay systems. First, with microgel electrophoresis (MGE), we observed graded, dose\u2010dependent, significant increases (<jats:italic>P<\/jats:italic> &lt; .0001) in the frequency of comet tails of fragmented DNA when cells were treated with morphine alone (5 \u00d7 10<jats:sup>\u22129<\/jats:sup>M up to 10<jats:sup>\u22127<\/jats:sup>M) or when co\u2010treated with the more potent mutagen, ethylmethanesulfonate (EMS). There were also dose\u2010dependent increases in the lengths and densities of the comet tails observed. These findings were confirmed by a series of MGE experiments in which several days of morphine exposure preceded a 2\u2010hr pulse of EMS. Second, mutant frequency (MF) assays also indicated significant opiate effects. These studies required separate assessment of cloning efficiencies and the frequencies of TG\u2010resistant, HPRT\u2010deficient mutant clones under four test conditions: no treatment, morphine alone for 4 days, morphine plus EMS, and EMS alone. Prior to the treatment phase, aminopterin was used to eliminate background HPRT mutations. The medium was changed after the treatment phase, the cells were allowed to express mutant pheno\u2010types, and then TG was added and resistant mutant clones counted after 16 days. The background MF level for controls and for cells treated with EMS alone were negligible at 5.12 \u00d7 10<jats:sup>\u22128<\/jats:sup> and 7.25 \u00d7 10<jats:sup>\u22128<\/jats:sup>, respectively. In the cells treated with morphine alone or morphine plus EMS, MF levels increased very significantly (<jats:italic>P<\/jats:italic> &lt; .001) by &gt;100\u2010fold to 5.1 \u00d7 10<jats:sup>\u22126<\/jats:sup> and 7.0 \u00d7 10<jats:sup>\u22126<\/jats:sup>, respectively. Cloning efficiency also decreased significantly with both morphine\u2010exposed conditions. Preliminary analysis with the single strand conformational polymorphism (SSCP) procedure following 6\u2010thioguanine (TG) selection, also confirmed the occurrence of Exon 3 mutants of the HPRT gene in cells exposed to morphine plus EMS. It appears that brief EMS exposure can be repaired, whereas, if morphine exposure persists through one or more cell cycles, direct or indirect mutagenesis is initiated. \u00a9 1994 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/em.2850230107","type":"journal-article","created":{"date-parts":[[2007,2,21]],"date-time":"2007-02-21T19:02:56Z","timestamp":1172084576000},"page":"37-44","source":"Crossref","is-referenced-by-count":24,"title":["Detection of opiate\u2010enhanced increases in DNA damage, HPRT mutants, and the mutation frequency in human HUT\u201078 cells"],"prefix":"10.1002","volume":"23","author":[{"given":"David A.","family":"Shafer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiping","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur","family":"Falek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,7,14]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/19.2.405"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0027-5107(90)90023-W"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/84.24.1922"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19920915)70:4 <1727::AID-CNCR2820701613>3.0.CO;2-P"},{"key":"e_1_2_1_6_1","volume-title":"Progress in Mutation Research","author":"Crespi CL","year":"1985"},{"key":"e_1_2_1_7_1","first-page":"95","article-title":"Morphine depression of T\u2010cell E\u2010rosetting: Definition of the process","volume":"44","author":"Donahoe RM","year":"1985","journal-title":"Fed Proc"},{"key":"e_1_2_1_8_1","first-page":"289","volume-title":"Enkephalins and Endorphins: Stress and the Immune System","author":"Donahoe RM","year":"1985"},{"key":"e_1_2_1_9_1","first-page":"105","article-title":"Opiates as immunocompromising drugs: The evidence and possible mechanisms","volume":"90","author":"Donahoe RM","year":"1988","journal-title":"NIDA Res Monograph"},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(86)90109-1"},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1972.01750280077013"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1980.01780150117012"},{"key":"e_1_2_1_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90186-I"},{"key":"e_1_2_1_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1.1.34"},{"key":"e_1_2_1_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(78)92218-3"},{"key":"e_1_2_1_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.10.4623"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(78)92000-7"},{"key":"e_1_2_1_18_1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1182\/blood.V67.4.849.849","article-title":"Chromosomal fragile sites and cancer\u2010specific rearrangements","volume":"67","author":"Le Beau MM","year":"1986","journal-title":"Blood"},{"key":"e_1_2_1_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.11.5769"},{"key":"e_1_2_1_20_1","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.4049\/jimmunol.125.6.2539","article-title":"Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: In vivo evidence for opiate receptor sites on T\u2010lymphocytes","volume":"125","author":"McDonough RJ","year":"1980","journal-title":"J Immunol"},{"key":"e_1_2_1_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/2.2.87"},{"key":"e_1_2_1_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(89)90129-8"},{"key":"e_1_2_1_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/335400a0"},{"key":"e_1_2_1_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(197906)43:6<2315::AID-CNCR2820430622>3.0.CO;2-J"},{"key":"e_1_2_1_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/5.6.593"},{"key":"e_1_2_1_26_1","first-page":"835","volume-title":"The Cytogenetics of Mammalian Autosomal Rearrangements","author":"Sandberg AA","year":"1988"},{"key":"e_1_2_1_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-4889-4_19"},{"key":"e_1_2_1_28_1","unstructured":"ShaferDA XieY FalekA(1993):Microgel electrophoresis detection of DNA damage in human cells exposed to in vitro to physiological doses of opiates and phenothiazines. 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