Marked increases in hepatic NAD(P)H:oxidoreductase gene transcription and mRNA levels correlated with a mouse chromosome 7 deletion.
The NAD(P)H:menadione oxidoreductase gene (Nmo-1) codes for a quinone reductase (also called DT diaphorase; EC 1.6.99.2) believed to play a central role in protection against oxidative stress. We have studied mice with a radiation-induced chromosomal deletion involving the albino locus (c) on chromosome 7 and found that Nmo-1 mRNA levels and the rate of Nmo-1 gene transcription are markedly increased (greater than 100-fold and greater than 12-fold, respectively) in the untreated c14CoS/c14CoS deletion homozygote, compared with the untreated Cch/Cch wild-type and the Cch/C14CoS heterozygote. These data suggest that a gene located on chromosome 7 encodes a trans-acting regulatory factor that might be a negative effector of the Nmo-1 gene, which we show here is located on chromosome 8 approximately 1.4 centimorgans (about 1000 kilobase pairs) from the Es-2 gene. Conversely, there are no detectable basal levels of cytochrome P1450 (Cyp1a1 gene) or cytochrome P3450 (Cyp1a2 gene) mRNA, indicating that the regulation of basal expression of the Cyp1a1 and Cyp1a2 genes is distinct from that of the Nmo-1 gene. Moreover, the Cyp1a1 and Cyp1a2 genes and the Nmo-1 gene are induced by tetrachlorodibenzo-p-dioxin in the cch/cch, cch/c14CoS, and c14CoS/c14CoS mice. The mechanism of tetrachlorodibenzo-p-dioxin inducibility of the Cyp1a1, Cyp1a2, and Nmo-1 genes is, therefore, independent of the mechanism of Nmo-1 gene activation in untreated c14CoS/c14CoS mice.
Petersen
D D
DD
Laboratory of Developmental Pharmacology, National Institute of Child Health and Human Development, Bethesda, MD 20892.
Gonzalez
F J
FJ
Rapic
V
V
Kozak
C A
CA
Lee
J Y
JY
Jones
J E
JE
Nebert
D W
DW
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D015139:Blotting, Southern; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D005333:Fetus; D005786:Gene Expression Regulation; D005796:Genes / Q000187:drug effects; D005809:Genes, Regulator; D008099:Liver / Q000201:enzymology / Q000254:growth & development; D051379:Mice; D008817:Mice, Mutant Strains; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase; D009693:Nucleic Acid Hybridization; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011808:Quinone Reductases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D011808:Quinone Reductases; D009252:NADPH Dehydrogenase