Induction of Heme Oxygenase‐1 mRNA and Protein in Neocortex and Cerebral Vessels in Alzheimer's Disease

Premkumar, Daniel R.; Smith, Mark A.; Richey, Peggy L.; Petersen, Robert B.; Castellani, Rudy J.; Kutty, R. Krishnan; Wiggert, Barbara; Perry, George; Kalaria, Rajesh N.

doi:10.1046/j.1471-4159.1995.65031399.x

Cited by 201 publications

(95 citation statements)

References 17 publications

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“…Interestingly, the in vitro toxicity of amyloid-β is also abolished by pretreatment with metal chelators [53]. Data from our laboratory and others also indicate that heme oxygenase-1 (HO-1) is induced in AD brains [54,55]. HO-1 catalyzes the conversion of heme to biliverdin and iron.…”

Section: Redox-active Metalsmentioning

confidence: 78%

Nucleic acid oxidation in Alzheimer disease

Moreira

Nunomura

Nakamura

et al. 2008

Free Radical Biology and Medicine

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187

113

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Increasing evidence suggests that oxidative stress is intimately associated with Alzheimer disease pathophysiology. Nucleic acids (nuclear DNA, mitochondrial DNA, and RNA) are one of the several cellular macromolecules damaged by reactive oxygen species, particularly the hydroxyl radical. Because neurons are irreplaceable and survive as long as the organism does, they need elaborate defense mechanisms to ensure their longevity. In Alzheimer disease, however, an accumulation of nucleic acid oxidation is observed, indicating an increased level of oxidative stress and/or a decreased capacity to repair the nucleic acid damage. In this review, we present data supporting the notion that mitochondrial and metal abnormalities are key sources of oxidative stress in Alzheimer disease. Furthermore, we outline the mechanisms of nucleic acid oxidation and repair. Finally, evidence showing the occurrence of nucleic acid oxidation in Alzheimer disease will be discussed.

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Section: Redox-active Metalsmentioning

confidence: 78%

Nucleic acid oxidation in Alzheimer disease

Moreira

Nunomura

Nakamura

et al. 2008

Free Radical Biology and Medicine

Self Cite

187

113

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“…Studies in a transgenic mouse model of AD showed that the expression of CuZn superoxide dismutase and HO-1 is significantly higher when compared with control mice [54]. Using immunolabeling or PCR techniques, a robust overexpression of HO-1 proteins, or mRNA in brain samples of sporadic AD when compared with age-matched controls was observed [58,64,66,68].…”

Section: Discussionmentioning

confidence: 99%

“…Heme oxygenase-1 (HO-1) is an antioxidant enzyme that degrades heme into biliverdin, iron and carbon monoxide and is one of the most sensitive and selective indicators of the cellular oxidative stress response. It has been shown that brains of AD patients present an increase of both HO-1 mRNA and protein [58,65] which co-localizes and parallels the expression of the altered form of tau characteristic of AD [76,77].…”

Section: −•mentioning

confidence: 99%

Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts

Moreira

Harris

Zhu

et al. 2007

JAD

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173

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Abstract. In this study, we evaluated the effect of lipoic acid (LA) and N -acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, N ε -(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1 mM) and/or N -acetyl cysteine (100 µM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously. AD-type changes could be generated in control fibroblasts using N -methylprotoporphyrin to inhibit cytochrome oxidase assembly indicating that the the oxidative damage observed was associated with mitochondrial dysfunction. The effects of N -methylprotoporphyrine were reversed or attenuated by both lipoic acid and N -acetyl cysteine. These data suggest mitochondria are important in oxidative damage that occurs in AD. As such, antioxidant therapies based on lipoic acid and N -acetyl cysteine supplementation may be promising.

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“…For the determination of heme oxygenase 1 (HO-1) mRNA levels, a real-time PCR technique was used (for review, see Bustin, 2000). A 271-base pair fragment of the HO-1 cDNA was amplified by using the LightCycler System (Roche Molecular Biochemicals, Indianapolis, IN) with the primers of Premkumar et al (1995). Quantitation was achieved by monitoring the fluorescence of intercalated SYBR Green I at each cycle.…”

Section: Methodsmentioning

confidence: 99%

Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[a]pyrene Is Diminished by Arsenite

Spink

Katz²,

Hussain³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Polycyclic aromatic hydrocarbons (PAHs) and metals are often environmental cocontaminants, yet there have been relatively few studies of combined effects of PAHs and metals on cytochrome P450 (P450)-catalyzed metabolism. We examined the effects of NaAsO 2 in combination with benzo[a]pyrene (BAP) on CYP1A1 and CYP1B1 in T-47D human breast cancer cells by using estrogen metabolism as a probe of their activities. Exposure to BAP caused elevated rates of the 2-and 4-hydroxylation pathways of estrogen metabolism, indicating induction of both CYP1A1, an estradiol 2-hydroxylase, and CYP1B1, an estradiol 4-hydroxylase. BAP-induced metabolism peaked 9 to 16 h after exposure and returned to near-basal levels by 48 h. Concentration-response studies showed maximal induction of the 2-and 4-hydroxylation pathways at 3 M BAP; higher levels caused reduced rates of metabolism due to inhibition of CYP1A1 and CYP1B1. NaAsO 2 caused pronounced decreases in the induction of CYP1A1 and CYP1B1 by 3 M BAP because cotreatment with 10 M NaAsO 2 inhibited the rates of the 2-and 4-hydroxylation pathways by 86 and 92%, respectively. Western immunoblots showed diminished levels of BAP-induced CYP1A1 by coexposure to NaAsO 2 . The levels of the CYP1A1 and CYP1B1 mRNAs induced by BAP were not significantly affected by coexposure to NaAsO 2 ; however, heme oxygenase 1 mRNA levels were markedly induced by coexposure to BAP and NaAsO 2 . These results indicate a post-transcriptional inhibitory effect of arsenite on the expression of CYP1A1 and CYP1B1 in T-47D cells, possibly resulting from reduced heme availability.Among the environmental contaminants of most concern due to their toxicity, including carcinogenicity, are heavy metals, such as arsenic, lead, and mercury, and polycyclic aromatic hydrocarbons (PAHs 1 ) typified by benzo[a]pyrene (BAP). PAHs and heavy metals are often cocontaminants in the environment, yet there have been relatively few studies of the combined toxic and particularly the carcinogenic effects elicited by PAHs and heavy metals. The carcinogenicity of BAP and other PAHs is a consequence of their metabolic activation catalyzed by cytochromes P450 (P450) and epoxide hydrolase (Wood et al., 1976;Kapitulnik et al., 1978). Covalent adducts formed by the reaction of PAH diol epoxide metabolites with guanine in mutational hotspots of critical genes such as that of the p53 tumor suppressor (Denissenko et al., 1996), if not efficiently repaired, may initiate tumorigenesis.Several members of the P450 superfamily in conjunction with epoxide hydrolase have been shown to catalyze the metabolism of BAP to carcinogenic intermediates. In extrahepatic tissues, CYP1A1 and CYP1B1 are thought to be the most important enzymes in catalyzing the formation of mutagenic intermediates from BAP and a number of other PAHs, including several that are potent mammary gland carcinogens in rodents. CYP1B1 appears to be more active than CYP1A1 in the conversion of a number of PAHs to genotoxic intermediates (Shimada et al., 1996). In the presence...

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Induction of Heme Oxygenase‐1 mRNA and Protein in Neocortex and Cerebral Vessels in Alzheimer's Disease

Cited by 201 publications

References 17 publications

Nucleic acid oxidation in Alzheimer disease

Nucleic acid oxidation in Alzheimer disease

Lipoic Acid and N-acetyl Cysteine Decrease Mitochondrial-Related Oxidative Stress in Alzheimer Disease Patient Fibroblasts

Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[a]pyrene Is Diminished by Arsenite

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