Human NAD(P)H:quinone oxidoreductase induction in human hepatoma cells after exposure to industrial acrylates, phenolics, and metals.
Induction of the endogenous human NAD(P)H:quinone oxidoreductase (HQOR1) gene in the human hepatoma cell line HepG2 was measured at both the enzyme activity and RNA levels after exposure to a variety of industrial compounds. An RNA probe was designed that was complementary to portions of both the coding region and the 3'-nontranslated region unique to the largest (2.7-kilobase) HQOR1 transcript. Induction by three strong inducers of HQOR1 verified the utility of the antisense RNA probe. Ten industrial chemicals were evaluated as potential inducers, i.e. acrylonitrile, Sb2O3, BaO, CdCl2, CuCl, ethyl acrylate, methyl acrylate, MoO3, phenol, and toluene. Induction at the RNA level was about 2-fold higher than at the enzyme activity level except in the case of acrylonitrile, for which induction at the enzyme activity and RNA levels was similar. There was no preferential induction of the 2.7-kilobase transcript for any chemical tested, including 2,3,7,8-tetrachloro-dibenzo-p-dioxin, which had previously been reported to preferentially induce this transcript. Six of the 10 industrial chemicals, including four previously untested chemicals (phenol, Sb2O3, CuCl, and MoO3), were found to induce the HQOR1 gene. By comparison, previous studies in rodent systems failed to accurately predict the human HQOR1 gene response. Two chemicals previously shown to be inducers in rodent systems (methyl acrylate and CdCl2 failed to induce the HQOR1 gene. These results emphasize the importance of analyzing induction of the endogenous human gene, rather than simply extrapolating from rodent systems or gene fusion experiments.
Winner
E J
EJ
Department of Biochemistry, School of Medicine, University of Louisville, KY 40292, USA.
Prough
R A
RA
Brennan
M D
MD
D000181:Acrylonitrile / Q000494:pharmacology; D001551:Benz(a)Anthracenes / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis* / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D001551:Benz(a)Anthracenes; D002273:Carcinogens; D006873:Hydroquinones; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; C018855:2-tert-butylhydroquinone; C030935:benz(a)anthracene; D016660:NAD(P)H Dehydrogenase (Quinone); D000181:Acrylonitrile