Cellular Responses to Oxidative Stress: The [Ah] Gene Battery As a Paradigm

Abstract

A major source of oxidative stress in animals is plant stress metabolites, also termed phytoalexins. The aromatic hydrocarbon-responsive [Ah] gene battery is considered here as a model system in which we can study metabolically coordinated enzymes that respond to phytoalexin-induced oxidative stress. In the mouse, the [Ah] battery comprises at least six genes: two Phase I genes, CYPIAI and CYPIA2; and four Phase II genes, Nmo-1, Aldh-i, Ugt-1, and Gt-l. All six genes appear to be regulated positively by inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other ligands of the Ah receptor. In the absence of foreign inducer, the control of Nmo-l gene expression is independent of the control of CYPIAI and CYPIA2 gene expression. The radiation deletion homozygote c 4Cot/C14Co5mouse is lacking about 1.1 centiMorgans of chromosome 7. Although having no detectable CYPIAI or CYPIA2 activation, the untreated C14CI/C14Cos mouse exhibits markedly elevated transcripts of the Nmo-i gene and three growth arrest-and DNA damage-inducible (gadd) genes. These data suggest that the missing region on chromosome 7 in the C14CoS/C14CoS mouse contains a gene(s), which we propose to call Nmo-In, encoding a trans-acting factor(s) that is a negative effector of the Nmo-l and gadd genes. The three other [Ah] battery Phase II genes behave similarly to Nmo-1 in the C14CoS/C14CoS mouse. This coordinated response to oxidative stress and DNA damage, by way of the release of a mammalian battery of genes from negative control, bears an interesting resemblance to the SOS response in bacteria.

α-Tocopherol is an effective Phase II enzyme inducer: protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells

“…Phase II enzymes act on the oxygenated intermediates, usually by conjugating them with various endogenous moieties to produce extremely hydrophilic products that are easily excreted from the cell [31]. Phase II enzymes are regulated by a common upstream promoter regulatory element called the antioxidant-response element (ARE).…”

Phenobarbital induction of cytochrome P-450 gene expression

“…This general mechanism is common to a diverse class of endogenous lipophilic hormones and other activators of the steroid/thyroid receptor superfamily transcription factors, including steroid hormones, thyroid hormones, and retinoic acid (Evans, 1988). It is, apparently, also utilized by dioxin and other polycyclics in their interaction with the Ah receptor, leading to induction of family lA P-450, (Whitlock, 1986;Nebert et al, 1990;Landers & Bunce, 1991). A receptor-dependent induction mechanism such as this need not be direct; as, for instance, when an inducer-receptor complex activates transcription of one gene, whose product then induces the target gene of interest (cf.…”

Dioxin‐Activated AHR: Toxic Responses and the Induction of Oxidative Stress

“…Initial studies focused on the role of the microsomal enzymes, including the cytochrome P450 system [5,[13][14][15][16], in TCDD-induced lipid peroxidation, reduction in antioxidant enzymes, and modulation of reduced glutathione levels. The dioxin-inducible AHR battery of genes contains at least six genes in mice that play important roles in the toxic effects of TCDD and its congeners, including the production of oxidative stress [43]. At least two cytochrome P450 genes are involved [43][44][45][46][47][48][49][50] and are positively regulated by TCDD and other ligands that bind to the AHR.…”

“…The dioxin-inducible AHR battery of genes contains at least six genes in mice that play important roles in the toxic effects of TCDD and its congeners, including the production of oxidative stress [43]. At least two cytochrome P450 genes are involved [43][44][45][46][47][48][49][50] and are positively regulated by TCDD and other ligands that bind to the AHR. In general, CYP1A1 [45] and CYP1B1 [46], but not CYP1A2 [48], appeared to play critical roles in TCDD-induced oxidative stress.…”