Negative regulation of the murine cytosolic aldehyde dehydrogenase-3 (Aldh-3c) gene by functional CYP1A1 and CYP1A2 proteins.
We have examined enzyme activities and mRNA levels corresponding to aldehyde dehydrogenase-3 genes encoding cytosolic (ALDH3c) and microsomal (ALDH3m) forms. In contrast to negligible activities in the intact mouse liver, both ALDH3c and ALDH3m enzyme activities are inducible by benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mouse hepatoma Hepa-1c1c7 cell cultures. Constitutive mRNA levels of ALDH3c are virtually absent, whereas those of ALDH3m are substantial; using Hepa-1 mutant lines, we show that both ALDH3c and ALDH3m are TCDD-inducible by an Ah receptor-dependent mechanism. Basal mRNA levels of ALDH3c, but not those of ALDH3m, are strikingly elevated in untreated mutant cells lacking a functional CYP1A1 enzyme; low ALDH3c basal mRNA levels can be restored by introduction of a functional murine CYP1A1 or human CYP1A2 enzyme into these mutant cells. These data suggest that the TCDD induction process is distinct from the CYP1A1/CYP1A2 metabolism-dependent repression of constitutive gene expression; we suggest that this latter property classifies the Aldh-3c gene, but not the Aldh-3m gene, as a member of the murine [Ah] battery.
Vasiliou
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Department of Environmental Health, University of Cincinnati Medical Center, Ohio 45267-0056.
Puga
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Nebert
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D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D015342:DNA Probes; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D009693:Nucleic Acid Hybridization; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D015342:DNA Probes; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D001564:Benzo(a)pyrene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D000444:Aldehyde Dehydrogenase