Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

Koppaka, Vindhya; Thompson, David C.; Chen, Ying; Ellermann, Manuel; Nicolaou, K. C.; Juvonen, Risto O.; Petersen, Dennis R.; Deitrich, Richard A.; Hurley, Thomas D.; Vasiliou, Vasilis

doi:10.1124/pr.111.005538

Cited by 460 publications

(486 citation statements)

References 165 publications

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“…However, no direct comparison between GTN and ISDN in vivo with an ALDH2 inhibitor has been reported previously, although cyanamide has been used clinically for many years. 19) Interestingly, there is a difference in human polymorphisms at codon 487 (*1, GAA= glu: *2, AAA= Lys) of ALDH2 genotypes with high activity (*1/*1) and low activity (*2/*2). The pioneering work of Mackenzie et al 20) demonstrated attenuation of GTN-induced increase in human forearm blood flow in *1/*2 and *2/*2 populations and also in healthy volunteers (*1/*1) after disulfiram.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cyanamide, an Aldehyde Dehydrogenase Type 2 Inhibitor, on Glyceryl Trinitrate- and Isosorbide Dinitrate-Induced Vasodilation in Rabbit Excised Aorta and in Anesthetized Whole Animal

Ishibashi

Nomura-Nakamoto

Abe

et al. 2013

Biological & Pharmaceutical Bulletin

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The contribution of aldehyde dehydrogenase type 2 (ALDH2) to bioactivation of glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) was systematically examined in excised rabbit aorta and anesthetized whole animal with cyanamide, an ALDH2 inhibitor. In excised aortic preparation, the degree of inhibition by cyanamide in GTN-induced vasorelaxation (concentration ratio, calculated as EC 50 in the presence of cyanamide/EC 50 in the absence of cyanamide; 5.61) was twice that in ISDN-induced relaxation (2.78). However, the degree of inhibition by cyanamide, as assessed by the dose ratio (as described above, but calculated with doses) in anesthetized rabbits was 2.29 in GTN-induced hypotension (assessed by area under the curve (AUC) of 50 mmHg·min) and 7.68 in ISDN-induced hypotension. Thus, the inhibitor was 3 times more potent in ISDN-induced hypotension, a finding in conflict with to that obtained in excised aortic preparation. The rate of increase in plasma nitrite (NO 2 − ) concentration at certain hypotensive effect (50 mmHg·min of AUC) in the presence and absence of cyanamide (ΔNO 2 − ratio) was larger in ISDN-induced hypotension (15.01) than in GTN-induced hypotension (3.28). These results indicate that the bioactivation pathway(s) of GTN is ALDH2-dependent in aortic smooth muscle, while ADLH2-independent mechanism(s) largely take place in the whole body. In contrast, the activation mechanism(s) of ISDN is largely ALDH2-dependent in both aortic smooth muscle and whole body. Plasma NO 2 − may be derived from pathways other than the cyanamide-sensitive metabolic route.Key words glyceryl trinitrate; isosorbide dinitrate; cyanamide; rabbit; nitrite Glyceryl trinitrate (GTN) has been widely used in the treatment of ischemic heart disease for more than a century 1) and the main mechanism of its vascular action is the activation of the intracellular nitric oxide (NO) receptor enzyme, soluble guanylate cyclase, leading to increased bioavailability of guanosine 5′-cyclic monophosphate (cGMP) and activation of cGMP-dependent protein kinases and/or cyclic nucleotidegated ion channels.2) However, the mechanism of bioactivation of the agent, upstream of intracellular signal transduction, was not elucidated until recently.Another new concept argues that the high potency nitrate, GTN, is mainly bioactivated by mitochondrial aldehyde dehydrogenase type 2 (ALDH2) when used at low, clinically relevant concentrations (<1 µm, high affinity pathway), and this notion is supported by evidence from various laboratories. [3][4][5] On the other hand, the low potency nitrate, isosorbide dinitrate (ISDN), is suggested to be mainly metabolized by P450 in the endoplasmic reticulum, directly yielding nitric oxide. 5-7)Although the above scenarios are based on many molecular, biochemical, mechanical (excised vascular preparation) and whole animal studies, there are no systematic studies that include both excised vascular and whole animal preparations to elucidate the difference between GTN and ISDN in one species.The present study was de...

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Section: Discussionmentioning

confidence: 99%

Effects of Cyanamide, an Aldehyde Dehydrogenase Type 2 Inhibitor, on Glyceryl Trinitrate- and Isosorbide Dinitrate-Induced Vasodilation in Rabbit Excised Aorta and in Anesthetized Whole Animal

Ishibashi

Nomura-Nakamoto

Abe

et al. 2013

Biological & Pharmaceutical Bulletin

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“…The anti-cancer mechanisms of disulfiram are not limited to ALDH inhibition; principally, disulfiram is used to inhibit the proteasome and E3 ligases, and may also be a DNAdemethylating compound [140][141][142][143]. Disulfiram inhibits both ALDH1A1 and ALDH2 isoforms [138,144], and has shown anti-CSC effects in breast cancer and GBM [145,146]. Though the anti-CSC effects in the breast cancer studies have been mostly attributed to disulfiram's proteasome inhibition [146][147][148] in glioblastoma, ALDH inhibition by disulfiram re-sensitized Aldefluor+ cells to gemcitabine cytotoxicity [149].…”

Section: Aldehyde Dehydrogenase Inhibitorsmentioning

confidence: 99%

“…Known inhibitors of ALDHs include chloral hydrate, cyanamide, DEAB, gossypol, molinate, pargyline, and disulfiram [138]. Disulfiram has been used for decades to treat alcohol abuse, and recently its potential in cancer treatment has been investigated [139].…”

Section: Aldehyde Dehydrogenase Inhibitorsmentioning

confidence: 99%

Chemoresistance in Cancer Stem Cells and Strategies to Overcome Resistance

Thomas¹,

Coyle²,

Sultan³

et al. 2014

Chemotherapy

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In cancers, there exists a subpopulation of cells which are referred to as cancer stem cells (CSCs) or tumor initiating cells that have enhanced tumor-initiating capacity and metastatic potential, and drive tumor progression. Since the initial identification of acute myeloid leukemia CSCs in 1997, CSCs have been found in many types of cancer and have intrinsic resistance to the current chemotherapeutic strategies. With increased levels of detoxifying enzymes, enhanced DNA repair abilities, impressive efflux capacity, and a slower cell-cycle; CSCs present a formidable obstacle against effective chemotherapy. Several methods of specifically targeting CSCs have been developed in recent years, and these compounds have potential as adjuvant therapies. The following is a review of the mechanisms responsible for chemoresistance in CSCs, with an emphasis on potential strategies to overcome this resistance.

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“…The more commonly encountered enzymes involved in oxidation, reduction, and hydrolysis (phase I metabolism) include molybdenum cofactor-containing enzymes [aldehyde oxidase (AO) (Hutzler et al, 2013) and xanthine oxidase (Pryde et al, 2010)], flavin-containing monooxygenases (Hines et al, 1994), monoamine oxidase (Edmondson et al, 2009), reductases [carbonyl reductases (Forrest and Gonzalez, 2000) and aldo-keto reductases (Jin and Penning, 2007;Oppermann, 2007;Penning, 2015)], dehydrogenases [alcohol dehydrogenase (Bosron and Li, 1987;Jornvall et al, 2000) and aldehyde dehydrogenase (Marchitti et al, 2008;Koppaka et al, 2012)], and hydrolytic enzymes (esterases, proteases/peptidases, amidases, etc.) (Testa and Mayer, 2006;Uetrecht and Trager, 2007;Long and Cravatt, 2011;Yang et al, 2011;Bachovchin and Cravatt, 2012;Oda et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015

Cerny

2016

Drug Metabolism and Disposition

122

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In recent years, claims of increased involvement of non-cytochrome P450 (non-P450) enzymes in the metabolism of drugs have appeared in the literature. However, no temporal summaries of the contribution of non-P450 enzymes to the metabolism of drugs have been published. Using data from human radiolabeled absorption, distribution, metabolism, and excretion studies available for a set of 125 orally or intravenously administered small-molecule drugs approved by the United States Food and Drug Administration from 2006 to 2015, the contributions of P450 and non-P450 enzymes to the formation of major metabolites ( ‡10% of dose) were assessed and tabulated. Over this time frame, the involvement of P450 versus non-P450 enzymes in the formation of major metabolites is compared, and the individual non-P450 enzymes responsible are described. This analysis indicates that non-P450 enzymes contribute significantly to the metabolism of the 125 drugs analyzed. Approximately 30% of the metabolism of these drugs is carried out by non-P450 enzymes, with the predominant non-P450 enzymes identified being glucuronosyltransferases (11.7%), hydrolases (10.8%), carbonyl reductases (2.4%), and aldehyde oxidase (1.1%). Although significant, the relative contribution of non-P450 enzymes to drug metabolism does not appear to have increased dramatically over the last 10 years. As the current evaluation involves drugs which emerged from the discovery phase >10 years ago, this evaluation may not reflect the current or evolving situation in some research organizations; therefore, additional monitoring and assessment of the involvement of non-P450 enzymes in the metabolism of drugs will be conducted in the future.

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Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

Cited by 460 publications

References 165 publications

Effects of Cyanamide, an Aldehyde Dehydrogenase Type 2 Inhibitor, on Glyceryl Trinitrate- and Isosorbide Dinitrate-Induced Vasodilation in Rabbit Excised Aorta and in Anesthetized Whole Animal

Effects of Cyanamide, an Aldehyde Dehydrogenase Type 2 Inhibitor, on Glyceryl Trinitrate- and Isosorbide Dinitrate-Induced Vasodilation in Rabbit Excised Aorta and in Anesthetized Whole Animal

Chemoresistance in Cancer Stem Cells and Strategies to Overcome Resistance

Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015

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