The Ubiquitous Aldehyde Reductase (AKR1A1) Oxidizes Proximate Carcinogen <i>trans</i>-Dihydrodiols to <i>o</i>-Quinones:  Potential Role in Polycyclic Aromatic Hydrocarbon Activation

Palackal, Nisha; Burczynski, Michael E.; Harvey, Ronald G.; Penning, T.M.

doi:10.1021/bi010872t

Cited by 120 publications

(146 citation statements)

References 33 publications

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“…Its electrophilic and redox properties indicates that these metabolites may act as initiators and promoters and may explain the complete carcinogenicity of PAH. AKRs implicated in this pathway in human are aldehyde reductase AKR1A1, and AKR1C1-AKR1C4 (35,36). Apart from AKR1C4 all enzymes are expressed in lung tissue, but importantly AKR1C1 is induced by PAH and ROS suggesting that the balance of expression may favor this isoform upon prolonged PAH exposure (24).…”

Section: Figure 6 Role Of Human Akrs In Pah Activationmentioning

confidence: 99%

Introduction and Overview of the Aldo-Keto Reductase Superfamily

Penning

2003

ACS Symposium Series

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Aldo-Keto Reductases (AKRs) are a rapidly growing gene superfamily involved in the formation of hyperosmotic sugars, which can contribute to diabetic complications. They also metabolize reactive aldehydes, prostaglandins, steroid hormones, chemical carcinogens and drugs. These enzymes (>115) are generally monomeric, cytosolic, NAD(P)Hdependent-oxidoreductases, that share high sequence identity -(<40%) and similar three-dimensional-structures e.g., (α/β) 8 -barrels and belong to 14 families. For a complete listing of the 14 families visit: www.med.upenn.edu/akr. AKRs detoxify endogenous toxicants, e.g., cytotoxic/mutagenic bifunctional electrophiles derived from the decomposition of lipid hydroperoxides. AKRs also metabolize exogenous toxic substances. They play a role in tobacco-carcinogenesis since they catalyze the detoxication of nicotine derived nitrosaminoketones and activate polycyclic aromatic trans-dihydrodiols to yield reactive and redox active ortho-quinones. Discrete isozymes also detoxify mycotoxin metabolites, e.g., aflatoxin dialdehyde and protect against hepatocellular carcinoma. The aflatoxin reductases are induced by cancer chemopreventive agents, e.g., ethoxyquin. Evidence is mounting that AKRs are stress regulated genes and play a central role in the cellular response to osmotic, electrophilic and oxidative stress.

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Section: Figure 6 Role Of Human Akrs In Pah Activationmentioning

confidence: 99%

Introduction and Overview of the Aldo-Keto Reductase Superfamily

Penning

2003

ACS Symposium Series

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“…In humans P450s most implicated in PAH activation are 1A1, 1B1 (39,40) and the AKRs most involved are (1A1, 1C1-1C4) (20,21,41). These enzymes are differentially expressed and regulated.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography–Mass Spectrometry

Jiang

Gelhaus

Mangal

et al. 2007

Chem. Res. Toxicol.

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Benzo [a]pyrene (B[a]P), a representative polycyclic aromatic hydrocarbon (PAH), is metabolically activated by three enzymatic pathways; by peroxidases (e.g. cytochrome P450-peroxidase) to yield radical cations; by P4501A1/1B1 monoxygenation plus epoxide hydrolase to yield diol-epoxides; and by P4501A1/1B1 monoxygenation, epoxide hydrolase plus aldo-keto reductases (AKRs) to yield o-quinones. In humans, a major exposure site for environmental and tobacco smoke PAH is the lung, however, the profile of B[a]P metabolites formed at this site has not been well characterized. In this study, human bronchoalveolar H358 cells were exposed to B[a]P, and metabolites generated by peroxidase (B[a]P-1,6-and B[a]P-3,6-diones), from cytochrome P4501A1/1B1 monooxygenation (3-hydroxyl-B[a]P, B[a]P-7,8-and 9,10-trans-dihydrodiols, and B[a]P -r-7,t-8,t-9,c-10-tetrahydrotetrol (B[a]P -tetrol-1)), and from AKRs (B[a]P-7,8-dione) were detected and quantified by RP-HPLC-with in line photo-diode array and radiometric detection, and identified by LC-MS. Progress curves showed a lag-phase in the formation of 3-hydroxy-B[a]P, B[a]P-7,8-transdihydrodiol, B[a]P-tetraol-1 and B[a]P-7,8-dione over 24 h. Northern blot analysis showed that B [a]P induced P4501B1 and AKR1C isoforms in H358 cells in a time-dependent manner providing an explanation for the lag-phase. Pretreatment of H358 cells with 10 nM 2,3,7,8-tetrachlorodibenzop-dioxin, (TCDD) eliminated this lag-phase, but did not alter the levels of the individual metabolites observed, suggesting that both B[a]P and TCDD induction ultimately yield the same B[a]P-metabolic profile. The one exception was B[a]P-3,6-dione which was formed without a lag-phase in the absence and presence of TCDD, suggesting that the peroxidase responsible for its formation was neither P4501A1 nor 1B1. Candidate peroxidases that remain include PGH synthases and uninduced P450 isoforms. This study shows that the P4501A1/1B1 and AKR pathways are inducible in human lung cells and that the peroxidase pathway was not. It also provides evidence that each of the pathways of PAH-activation yield their distinctive metabolites in H358 human lung cells and that each pathway may contribute to the carcinogenic process.

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“…The levels of 7-ethoxyresorufin (EROD), 7-methoxyresorufin (MROD), 7-pentoxyresorufin (PROD) O-dealkylases, and 7-benzyloxyresorufin O-dearylase (BROD) activity were determined at 37°C using fluorimetric determination of resorufin [9,51] 7-Penthoxyresorufin O-dealkylase PROD CYP2B [9,50] 7-Benzyloxyresorufin O-dearylase BROD CYP2B, CYP3A [9,50] 7-Methoxy-4-trifluoromethyl-coumarin demethylase MFCD CYP2C [13,40] 6-Chlorzoxazone hydroxylase CXOH CYP2E1, (CYP1A) [39,44] Thiobenzamide oxidase TBSO FMO [10] D,L-glyceraldehyde reductase GALR AKR1A [23] Metyrapone reductase METR (mic, cyt) 11b-HSD 1, AKR1C4, CBR [30] 4-Pyridine-carboxaldehyde reductase PCAR (mic, cyt) 3a-HSD, AKR1A, AKR1C [37] Daunorubicin reductase (pH 8.5) DAUR8 AKR1A [36] Daunorubicin reductase (pH 6.0) DAUR6 AKR1C2, CBR [16,36] Acenaphthenol dehydrogenase ANDH AKR1C1-4 [8,38] Oracin dehydrogenase ORDH (mic, cyt) 11b-HSD 1, AKR1C1-4, CBR [48,52] p-Nitrophenol-UGT UGT UGT [32] 1-Chloro-2,4-dinitrobenzene-GST GST GST [19] foxide, DMSO). Assays were performed using the Perkin-Elmer luminescence spectrophotometer LS 50B, with excitation and emission wavelengths of 530 nm and 585 nm, respectively.…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…Spectrophotometric determination (340 nm, 25°C) of NADPH consumption served as the assessment of reductase activities [16,23,30,36,37].…”

Section: Enzyme Assaysmentioning

confidence: 99%

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

Bártíková

Křížová

Štěpničková

et al. 2010

Pharmacological Reports

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Abstract:The effect of flubendazole (FLU) therapy on in vitro FLU biotransformation and the activities of selected biotransformation enzymes were investigated in male and female lambs. Four experimental groups were used: control (untreated) ewes and rams and FLU-treated ewes and rams (orally, 15 mg/kg per day, for three consecutive days). Subcellular fractions were prepared from liver and intestinal mucosa 24 h after the final dosage was administered. Activities of cytochromes P450 (CYP), flavine monooxygenases (FMO), carbonyl reducing enzymes, UDP-glucuronosyl transferase (UGT) and glutathione S-transferase were tested. Significant gender differences were observed for FMO-mediated activity (2-fold higher in ram lambs) and UGT activity (up to 30% higher in ewe lambs), but no gender differences were observed in FLU metabolism. FLU-treatment of lambs moderately changed the activities of some CYPs, FMO, and UGT in liver microsomes. In vitro FLU reduction was not altered in the liver, but was slightly higher in the small intestine of FLU pre-treated lambs. This correlated with the higher carbonyl reductase activities measured in the gut mucosa of these animals.

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The Ubiquitous Aldehyde Reductase (AKR1A1) Oxidizes Proximate Carcinogen trans-Dihydrodiols to o-Quinones: Potential Role in Polycyclic Aromatic Hydrocarbon Activation

Cited by 120 publications

References 33 publications

Introduction and Overview of the Aldo-Keto Reductase Superfamily

Introduction and Overview of the Aldo-Keto Reductase Superfamily

Metabolism of Benzo[a]pyrene in Human Bronchoalveolar H358 Cells Using Liquid Chromatography–Mass Spectrometry

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

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