“Oxidative stress” response in liver of an untreated newborn mouse having a 1.2-centimorgan deletion on chromosome 7

Abstract

The c 14CoS c 14CoS mouse has a homozygous deletion of about 1.2 cM on chromosome 7 that includes the albino ( c) locus. The untreated 14CoS 14CoS newborn has been reported to exhibit a marked transcriptional activation of the hepatic NAD(P)H:menadione oxidoreductase ( Nmo-1; DT diaphorase; quinone reductase; azo dye reductase) gene, as well as elevated UDP glucuronosyl-transferase (UGTI ∗06) and glutathione transferase (GT1) activities, when compared with the c ch c ch wild-type and the c ch c 14CoS heterozygote. We show here that the newborn hepatic activities of seven enzymes that play a role in the oxidative stress response—NMO1, UGT1 ∗06, GT1, copper-zinc superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase—are increased 1.5- to 25-fold in 14CoS 14CoS , as compared with ch ch and ch 14CoS mice. The activities of four additional enzymes having no known association with the oxidative stress response—benzo[a]pyrene hydroxylase (CYP1A1, cytochrome P 1450), acetanilide 4-hydroxylase (CYP1A2, cytochrome P 3450), lactate dehydrogenase (LDH), and NADPH-cytochrome c reductase—are not significantly different among the three genotypes. These data suggest that there exists an “oxidative stress” response in the untreated 14CoS 14CoS newborn. We postulate that a chromosome 7 regulatory gene, which we have named Nmo-1 n, might encode a trans -acting n egative effector of the Nmo-1 gene, and genes corresponding to the other elevated enzymic activities described above. When both copies of Nmo-1 n are deleted, as is the case in 14CoS 14CoS mice, a battery of genes involved in oxidative stress is released from negative control and becomes activated—despite the absence of any apparent oxidative insult by foreign chemicals.