Liang H C, Shertzer H G, Nebert D W
Department of Environmental Health, University of Cincinnati Medical Center, Ohio 45267-0056.
Biochem Biophys Res Commun. 1992 Feb 14;182(3):1160-5. doi: 10.1016/0006-291x(92)91853-i.
The c14CoS/c14CoS 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 (UGT106) and glutathione transferase (GT1) activities, when compared with the cch/cch wild-type and the cch/c14CoS heterozygote. We show here that the newborn hepatic activities of seven enzymes that play a role in the oxidative stress response--NMO1, UGT106, 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(1)450), acetanilide 4-hydroxylase (CYP1A2, cytochrome P(3)450), 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-1n, might encode a trans-acting negative effector of the Nmo-1 gene, and genes corresponding to the other elevated enzymic activities described above. When both copies of Nmo-1n 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.
c14CoS/c14CoS小鼠在7号染色体上有一个约1.2厘摩的纯合缺失，该区域包含白化病（c）基因座。据报道，未经处理的14CoS/14CoS新生小鼠的肝脏烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）：甲萘醌氧化还原酶（Nmo-1；DT黄递酶；醌还原酶；偶氮染料还原酶）基因呈现显著的转录激活，与cch/cch野生型和cch/c14CoS杂合子相比，其尿苷二磷酸葡萄糖醛酸基转移酶（UGT106）和谷胱甘肽转移酶（GT1）活性也有所升高。我们在此表明，与ch/ch和ch/14CoS小鼠相比，在氧化应激反应中起作用的七种酶——NMO1、UGT106、GT1、铜锌超氧化物歧化酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶和葡萄糖-6-磷酸脱氢酶——在14CoS/14CoS新生小鼠肝脏中的活性增加了1.5至25倍。另外四种与氧化应激反应无已知关联的酶——苯并[a]芘羟化酶（CYP1A1，细胞色素P(1)450）、对乙酰氨基酚4-羟化酶（CYP1A2，细胞色素P(3)450）、乳酸脱氢酶（LDH）和NADPH-细胞色素c还原酶——在三种基因型之间没有显著差异。这些数据表明，未经处理的14CoS/14CoS新生小鼠中存在一种“氧化应激”反应。我们推测，7号染色体上的一个调控基因，我们将其命名为Nmo-1n，可能编码Nmo-1基因以及上述其他升高的酶活性所对应的基因的反式作用负效应子。当Nmo-1n的两个拷贝都缺失时，如在14CoS/14CoS小鼠中那样，一系列参与氧化应激的基因就会从负调控中释放出来并被激活——尽管没有任何外来化学物质明显的氧化损伤。
