Detoxification Of Toxic Aldehydes Research Articles

An alcohol dehydrogenase 3 (ADH3) from Entamoeba histolytica is involved in the detoxification of toxic aldehydes

An alcohol dehydrogenase 3 (ADH3) from Entamoeba histolytica is involved in the detoxification of toxic aldehydes

Benzopyrazines: Synthesis, Characterization and Evaluation as Aldose Reductase Inhibitors

Role of aldose reductase (ALR2) in diabetic complications such as retinopathy, nephropathy, neuropathy, and cataract <i>etc</i>. is well-evident. ALR2 in the first step of polyol pathway reduces glucose to sorbitol whose elevated level leads to diabetic cataract, characterize by clouding of the lens in the eye that affects vision. Inhibition of ALR2 enzyme with small molecules as inhibitor is a rapid approach for diabetic management. In the present study the synthetic route to synthesize desired benzopyrazines and a library of sixteen (16) methyl benzopyrazines were screened against aldose reductase. From the bioactivity results, the 3'-hydroxyphenyl benzopyrazine 6l was found most active (IC₅₀ = 1.34 ± 0.07 <i>µ</i>M) while 3'-bromophenyl analogue 6i showed comparable activity for ALR2 (IC₅₀ = 3.48 ± 0.66 <i>µ</i>M) as compared to standard sorbinil (IC₅₀ = 3.14 ± 0.02 <i>µ</i>M). Both compounds (6l and 6i) showed excellent selectivity for ALR2 over aldehyde reductase (ALR1) which has important role in detoxification of toxic aldehydes. The structure of two regio-isomers were fully characterize by ¹H and ¹³C NMR two dimensional NMR techniques including COSY, NOESY, HSQC, and HMBC. Regio-isomers separation was proved to be difficult in different solvent systems. Only an isomer of 3'-bromo benzopyrazine 6i' was isolated that help to assign the structure of regioisomers from NMR data. All the benzopyrazines were fully characterized by using different spectral techniques including ¹H, ¹³C NMR, IR spectroscopy, and mass spectrometry.

ALDH2 Polymorphism and Ethanol Consumption: A Genetic-Environmental Interaction in Carcinogenesis.

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in the detoxification of toxic aldehydes, especially acetaldehyde, which is commonly considered as a carcinogen. ALDH2 mutation and impaired enzymatic activity will cause acetaldehyde accumulation and thus participate in the development of cancers. It deserves more attention since around 40% of East Asian population carry the inactive ALDH2 allele. Moreover, the risk for cancers will be even higher when ALDH2 mutation combined with heavy alcohol consumption, suggesting a genetic-environmental interaction in carcinogenesis. This may provide us with a potential target for cancer prevention and treatment.

Design, synthesis, and biological evaluation of new ALDH2 activators

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an important enzyme response for the metabolism or detoxification of toxic aldehydes, in particular acetaldehyde and 4-hydroxynonenal (4-HNE), which were important risk factors for acute alcoholism and stroke respectively. A special variant ALDH2∗2 with reduced enzymatic activity was carried by a high percentage of East Asians, especially Han Chinese, and that could increase the risk of these diseases further. Therefore, ALDH2 activators had important potential clinical values. N-benzylbenzamide compounds represented by Alda-1 were the only ALDH2-specific activators that have been reported so far. In this study, three new classes of compounds were modified from Alda-1 to improve their water-solubility and then drug-like properties. The results showed that all compounds had increased water solubility and two classes of compounds exhibited good activation activity. Among them, compound I-6 showed the best activity.

Aldehyde dehydrogenase 2 activation ameliorates cyclophosphamide-induced acute cardiotoxicity via detoxification of toxic aldehydes and suppression of cardiac cell death

Cyclophosphamide (CY)-induced acute cardiotoxicity is a common side effect which is dose dependent. It is reported that up to 20% of patients received high dose of CY treatment suffered from acute cardiac dysfunction. However, the effective intervention strategies and related mechanisms are still largely unknown. We aimed to investigate the effects of aldehyde dehydrogenase 2 (ALDH2), an important endogenous cardioprotective enzyme, on CY-induced acute cardiotoxicity and the underlying mechanisms. It was found that ALDH2 knockout (KO) mice were more sensitive to CY-induced acute cardiotoxicity, presenting as higher serum levels of creatine kinase-MB isoform and lactate dehydrogenase, and significantly reduced myocardial contractility compared with C57BL/6 (WT) mice. In addition, cardiac cell death, especially necrosis, was obviously increased in ALDH2 KO mice compared with WT mice after CY treatment. Furthermore, accumulation of toxic aldehydes such as acrolein and 4-HNE and reactive oxygen species (ROS) in the myocardium were significantly elevated after CY in ALDH2 KO mice. Importantly, ALDH2 activation by Alda-1 pretreatment markedly attenuated CY-induced accumulation of toxic aldehydes, cardiac cell death and cardiac dysfunction, without affecting CY's anti-tumor efficacy. In conclusion, the cardioprotective effects of ALDH2 activation against CY-induced acute cardiotoxicity are exerted via reducing toxic aldehydes accumulation and potentially interrupting the acrolein-ROS-aldehydes vicious circles, and thus alleviates myocardial cell death, without antagonizing the anti-tumor efficacy of CY. Therefore, ALDH2 might be a promising prevention and treatment target for CY-induced acute cardiotoxicity.

P3360Aldehyde dehydrogenase 2 ameliorates cyclophosphamide-induced cardiotoxicity through detoxification of toxic aldehydes and suppression of cell death

P3360Aldehyde dehydrogenase 2 ameliorates cyclophosphamide-induced cardiotoxicity through detoxification of toxic aldehydes and suppression of cell death

Thymoquinone binds and activates human salivary aldehyde dehydrogenase: Potential therapy for the mitigation of aldehyde toxicity and maintenance of oral health

Human salivary aldehyde dehydrogenase (hsALDH) is a very important anti-oxidant enzyme present in the saliva. It is involved in the detoxification of toxic aldehydes and maintenance of oral health. Reduced level of hsALDH activity is a risk factor for oral cancer development. Thymoquinone (TQ) has many pharmacological activities and health benefits. This study aimed to examine the activation of hsALDH by TQ. The effect of TQ on the activity and kinetics of hsALDH was studied. The binding of TQ with the enzyme was examined by different biophysical methods and molecular docking analysis. TQ enhanced the dehydrogenase activity of crude and purified hsALDH by 3.2 and 2.9 fold, respectively. The Km of the purified enzyme decreased and the Vmax increased. The esterase activity also increased by 1.2 fold. No significant change in the nucleophilicity of the catalytic cysteine residue was observed. TQ forms a strong complex with hsALDH without altering the secondary structures of the enzyme. It fits in the active site of ALDH3A1 close to Cys 243 and the other highly conserved amino acid residues which lead to enhancement of substrate binding affinity and catalytic efficiency of the enzyme. TQ is expected to give better protection from toxic aldehydes in the oral cavity and to reduce the risk of oral cancer development through the activation of hsALDH. Therefore, the addition of TQ in the diet and other oral formulations is expected to be beneficial for health.

Isoflurane preconditioning confers cardioprotection by activation of ALDH2.

The volatile anesthetic, isoflurane, protects the heart from ischemia/reperfusion (I/R) injury. Aldehyde dehydrogenase 2 (ALDH2) is thought to be an endogenous mechanism against ischemia-reperfusion injury possibly through detoxification of toxic aldehydes. We investigated whether cardioprotection by isoflurane depends on activation of ALDH2.Anesthetized rats underwent 40 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups: untreated controls, isoflurane preconditioning with and without an ALDH2 inhibitor, the direct activator of ALDH2 or a protein kinase C (PKCε) inhibitor. Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide. Isolated neonatal cardiomyocytes were treated with hypoxia followed by reoxygenation. Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2. In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2. Activation of ALDH2 and cardioprotection by isoflurane were substantially blocked by the PKCε inhibitor. Activation of ALDH2 by mitochondrial PKCε plays an important role in the cardioprotection of isoflurane in myocardium I/R injury.

Mechanisms Involved in the Protection of UV-induced Protein Inactivation by the Corneal Crystallin ALDH3A1

Various lines of evidence have shown that ALDH3A1 (aldehyde dehydrogenase 3A1) plays a critical and multifaceted role in protecting the cornea from UV-induced oxidative stress. ALDH3A1 is a corneal crystallin, which is defined as a protein recruited into the cornea for structural purposes without losing its primary function (i.e. metabolism). Although the primary role of ALDH3A1 in the metabolism of toxic aldehydes has been clearly demonstrated, including the detoxification of aldehydes produced during UV-induced lipid peroxidation, the structural role of ALDH3A1 in the cornea remains elusive. We therefore examined the potential contribution of ALDH3A1 in maintaining the optical integrity of the cornea by suppressing the aggregation and/or inactivation of other proteins through chaperone-like activity and other protective mechanisms. We found that ALDH3A1 underwent a structural transition near physiological temperatures to form a partially unfolded conformation that is suggestive of chaperone activity. Although this structural transition alone did not correlate with any protection, ALDH3A1 substantially reduced the inactivation of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal and malondialdehyde when co-incubated with NADP(+), reinforcing the importance of the metabolic function of this corneal enzyme in the detoxification of toxic aldehydes. A large excess of ALDH3A1 also protected glucose-6-phosphate dehydrogenase from inactivation because of direct exposure to UVB light, which suggests that ALDH3A1 may shield other proteins from damaging UV rays. Collectively, these data demonstrate that ALDH3A1 can reduce protein inactivation and/or aggregation not only by detoxification of reactive aldehydes but also by directly absorbing UV energy. This study provides for the first time mechanistic evidence supporting the structural role of the corneal crystallin ALDH3A1 as a UV-absorbing constituent of the cornea.

Sex-specific biotransformation and detoxification after xenobiotic exposure of primary cultured hepatocytes of European flounder ( Platichthys flesus L .)

Sex-specific effects of sublethal concentrations of known effective pro-oxidants such as 100, 200 and 400 μM benzo[ a]pyrene (B[ a]p), 50 μM nitrofurantoin (NF) and 100 μM hydrogen peroxide (H 2O 2) on biotransformation pathways were studied in isolated hepatocytes of immature female and male European flounder ( Platichthys flesus L.). Cell responses were assessed at the level of: (1) stress induction as measured by formation of reactive oxygen species (ROS), mainly superoxide radicals, and induction of cytochrome P450 (CYP450) biotransformation activity; (2) cellular antioxidant defences, both non-enzymatic (reduced glutathione) and enzymatic (DT-diaphorase (DTD) or quinone oxidoreductase, EC 1.6.99.2); (3) detoxification (aldehyde dehydrogenase (ALDH), EC 1.2.1.3); and (4) cellular damage as measured by reduced lysosomal membrane stability and cell death. As there is increasing evidence that 17-β-estradiol interferes with certain pathways of xenobiotic biotransformation, we additionally tested the effects of different concentrations of 17-β-estradiol (0.2–10 μM) alone and 17-β-estradiol (1 μM) in combination with 100 μM B[ a]p. Parameters were monitored after 1 and 9 days of exposure by quantitative image analysis of chromogenic or fluorogenic reaction products. Our study revealed sex-dependent differences in cellular stress responses. In hepatocytes of female flounder, biotransformation was slower and the capacity of non-enzymatic antioxidant defences and detoxification of toxic aldehydes was lower than in males. Additional administration of 17-β-estradiol enlarged these differences between the sexes with respect to biotransformation activity and antioxidant defence in xenobiotic-induced injury. These findings may explain the higher susceptibility of female flounder to toxic and carcinogenic compounds in the marine environment.