Protection Against Aflatoxin B<sub>1</sub>-Induced Cytotoxicity by Expression of the Cloned Aflatoxin B<sub>1</sub>-Aldehyde Reductases Rat AKR7A1 and Human AKR7A3

Bodreddigari, Sridevi; Jones, Laundette Knight; Egner, Patricia A.; Groopman, John D.; Sutter, Carrie Hayes; Roebuck, Bill D.; Guengerich, F. Peter; Kensler, Thomas W.; Sutter, Thomas R.

doi:10.1021/tx7004458

Cited by 31 publications

(21 citation statements)

References 37 publications

(75 reference statements)

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“…They may also be enzymatically hydrolyzed, and then detoxified to a dialchohol 29,30. Enzymes involved in both activation and detoxification of aflatoxin are polymorphic, and can therefore influence the toxic insult of exposure 31.…”

Section: Methodsmentioning

confidence: 99%

Aflatoxin Exposure During Pregnancy, Maternal Anemia, and Adverse Birth Outcomes

Smith

Prendergast

Turner

et al. 2017

The American Society of Tropical Medicine and Hygiene

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Pregnant women and their developing fetuses are vulnerable to multiple environmental insults, including exposure to aflatoxin, a mycotoxin that may contaminate as much as 25% of the world food supply. We reviewed and integrated findings from studies of aflatoxin exposure during pregnancy and evaluated potential links to adverse pregnancy outcomes. We identified 27 studies (10 human cross-sectional studies and 17 animal studies) assessing the relationship between aflatoxin exposure and adverse birth outcomes or anemia. Findings suggest that aflatoxin exposure during pregnancy may impair fetal growth. Only one human study investigated aflatoxin exposure and prematurity, and no studies investigated its relationship with pregnancy loss, but animal studies suggest aflatoxin exposure may increase risk for prematurity and pregnancy loss. The fetus could be affected by maternal aflatoxin exposure through direct toxicity as well as indirect toxicity, via maternal systemic inflammation, impaired placental growth, or elevation of placental cytokines. The cytotoxic and systemic effects of aflatoxin could plausibly mediate maternal anemia, intrauterine growth restriction, fetal loss, and preterm birth. Given the widespread exposure to this toxin in developing countries, longitudinal studies in pregnant women are needed to provide stronger evidence for the role of aflatoxin in adverse pregnancy outcomes, and to explore biological mechanisms. Potential pathways for intervention to reduce aflatoxin exposure are urgently needed, and this might reduce the global burden of stillbirth, preterm birth, and low birthweight.

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Section: Methodsmentioning

confidence: 99%

Aflatoxin Exposure During Pregnancy, Maternal Anemia, and Adverse Birth Outcomes

Smith

Prendergast

Turner

et al. 2017

The American Society of Tropical Medicine and Hygiene

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“…As such this reaction prevents the aldehydes from forming Schiff’s bases with lysine residues and can reduce the hepatotoxicity of aflatoxin [78]. In addition the AKR7A2 is the major succinic semialdehyde reductase in the CNS and is thus involved in GABA metabolism [79].…”

Section: Human Akrs and Diseasementioning

confidence: 99%

The aldo-keto reductases (AKRs): Overview

Penning

2015

Chemico-Biological Interactions

388

353

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The aldo-keto reductase (AKR) protein superfamily contains > 190 members that fall into 16 families and are found in all phyla. These enzymes reduce carbonyl substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation byproducts. Exceptions include the reduction of steroid double bonds catalyzed by AKR1D enzymes (5β-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the (β-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening. AKRs are usually 37 kDa monomers, have an (α/β)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. AKRs catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last. In enzymes that favor NADPH, the rate of release of NADP+ is governed by a slow isomerization step which places an upper limit on kcat. AKRs retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117 (AKR1C9 numbering). There is conservation of the catalytic mechanism with short-chain dehydrogenases/reductases (SDRs) even though they show different protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1-1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively. Inhibitor programs exist worldwide to target each of these enzymes to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1 enzymes are implicated in defects in the development of male genitalia and bile acid deficiency, respectively, and occur in evolutionary conserved amino acids. The human AKRs have a large number of nsSNPs and splice variants, but in many instances functional genomics is lacking. AKRs and their variants are now poised to be interrogated using modern genomic and informatics approaches to determine their association with human health and disease.

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“…58,59 Human aflatoxin dialdehyde reductases AKR7A2 and AKR7A3 protect against products of lipid peroxidation and aflatoxin dialdehyde in cell lines, respectively. 50,60 Each of the genes for these enzymes contained AREs. Knockdown of Nrf2 in HepG2 cells led to a reduction of AKR7A3 mRNA and AKR7A3 protein and increased sensitivity to acetaminophen-induced cytotoxicity.…”

Section: Evidence That Human Akr Genes Are Regulated By Aresmentioning

confidence: 99%

Aldo-Keto Reductase Regulation by the Nrf2 System: Implications for Stress Response, Chemotherapy Drug Resistance, and Carcinogenesis

Penning

2016

Chem. Res. Toxicol.

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Human aldo-keto reductases (AKRs) are NAD(P)H-dependent oxidoreductases that convert aldehydes and ketones to primary and secondary alcohols for subsequent conjugation reactions and can be referred to as “phase 1” enzymes. Among all the human genes regulated by the Keap1/Nrf2 pathway, they are consistently the most overexpressed in response to Nrf2 activators. Although these enzymes play clear cytoprotective roles and deal effectively with carbonyl stress, their upregulation by the Keap1/Nrf2 pathway also has a potential dark-side, which can lead to chemotherapeutic drug resistance and the metabolic activation of lung carcinogens (e.g., polycyclic aromatic hydrocarbons). They also play determinant roles in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone metabolism to R- and S-4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol. The overexpression of AKR genes as components of the “smoking gene” battery raises the issue as to whether this is part of a smoking stress response or acquired susceptibility to lung cancer. Human AKR genes also regulate retinoid, prostaglandin, and steroid hormone metabolism and can regulate the local concentrations of ligands available for nuclear receptors (NRs). The prospect exists that signaling through the Keap1/Nrf2 system can also effect NR signaling, but this has remained largely unexplored. We present the case that chemoprevention through the Keap1/Nrf2 system may be context dependent and that the Nrf2 “dose-response curve” for electrophilic and redox balance may not be monotonic.

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Protection Against Aflatoxin B₁-Induced Cytotoxicity by Expression of the Cloned Aflatoxin B₁-Aldehyde Reductases Rat AKR7A1 and Human AKR7A3

Cited by 31 publications

References 37 publications

Aflatoxin Exposure During Pregnancy, Maternal Anemia, and Adverse Birth Outcomes

Aflatoxin Exposure During Pregnancy, Maternal Anemia, and Adverse Birth Outcomes

The aldo-keto reductases (AKRs): Overview

Aldo-Keto Reductase Regulation by the Nrf2 System: Implications for Stress Response, Chemotherapy Drug Resistance, and Carcinogenesis

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Protection Against Aflatoxin B1-Induced Cytotoxicity by Expression of the Cloned Aflatoxin B1-Aldehyde Reductases Rat AKR7A1 and Human AKR7A3

Cited by 31 publications

References 37 publications

Aflatoxin Exposure During Pregnancy, Maternal Anemia, and Adverse Birth Outcomes

Aflatoxin Exposure During Pregnancy, Maternal Anemia, and Adverse Birth Outcomes

The aldo-keto reductases (AKRs): Overview

Aldo-Keto Reductase Regulation by the Nrf2 System: Implications for Stress Response, Chemotherapy Drug Resistance, and Carcinogenesis

Contact Info

Product

Resources

About

Protection Against Aflatoxin B₁-Induced Cytotoxicity by Expression of the Cloned Aflatoxin B₁-Aldehyde Reductases Rat AKR7A1 and Human AKR7A3