Aldehyde dehydrogenase

About: Aldehyde dehydrogenase is a research topic. Over the lifetime, 3365 publications have been published within this topic receiving 107683 citations.

RNA-Seq Profiling of Intestinal Expression of Xenobiotic Processing Genes in Germ-Free Mice

Abstract: Intestinal bacteria can affect xenobiotic metabolism through both direct bacterial enzyme-catalyzed modification of the xenobiotics and indirect alterations of the expression of host genes. To determine how intestinal bacteria affect the expression of host xenobiotic-processing genes (XPGs), the mRNA profiles of 303 XPGs were characterized by RNA sequencing in four intestinal sections and compared with that in the liver from adult male conventional (CV) and germ-free (GF) mice. Fifty-four XPGs were not expressed in the intestine of either CV or GF mice. The GF condition altered the expression of 116 XPGs in at least one intestinal section but had no effect on 133 XPGs. Many cytochrome P450 family members such as Cyp1a, Cyp2b10, Cyp2c, and most Cyp3a members, as well as carboxylesterase (Ces) 2a were expressed lower in the intestine of GF than CV mice. In contrast, GF mice had higher intestinal expression of some phase I oxidases (alcohol dehydrogenase 1, aldehyde dehydrogenase a1l1 and 4a1, as well as flavin monooxygenase 5) and phase II conjugation enzymes (UDP-glucuronosyltransferase 1a1, and sulfotransferase 1c2, 1d1, and 2b1). Several transporters in the intestine, such as bile acid transporters (apical sodium-dependent bile acid transporter, organic solute transporter α and β), peptide transporter 1, and multidrug and toxin extrusion protein 1, exhibited higher expression in GF mice. In conclusion, lack of intestinal bacteria alters the expression of a large number of XPGs in the host intestine, some of which are section specific. Cyp3a is downregulated in both the liver and intestine of GF mice, which probably contributes to altered xenobiotic metabolism.

Application of structure–activity relationships to investigate the molecular mechanisms of hepatocyte toxicity and electrophilic reactivity of α,β-unsaturated aldehydes

Abstract: Covalent binding of reactive electrophiles to cellular targets is a molecular interaction that has the potential to initiate severe adverse biological effects. Therefore, a measure for electrophilic reactivity with biological nucleophiles could serve as an important correlate to toxic effects such as hepatocyte death. To determine if electrophile reactivity correlates with rat hepatocyte cytotoxicity, the inherently electrophilic alpha,beta-unsaturated aldehydes were chosen for investigation. Reactivity was measured with simple assays that used glutathione, a soft nucleophile, and butylamine, a harder nucleophile, as models for protein thiol and amine nucleophilic sites, respectively. Despite their higher reactivity with thiols, a linear relationship was only observed between hepatocyte cytotoxicity and amine reactivity. Structure-activity relationships were also investigated for hepatocyte toxicity, and results showed toxicity was well modelled by log P and electronic parameters E(LUMO) and partial charge of the carbonyl carbon (C'(carb)). Hydrophobicity and electronic descriptors were only significant in separate distinct models, suggesting that there were simultaneously occurring mechanisms that affected toxicity. Log P was linked to the ease of oxidation by a microsomal aldehyde dehydrogenase enzyme, while the electronic descriptors and amine reactivity were linked to direct alkylation. Even with the presence of electrophile characteristics, alpha,beta-unsaturated aldehyde hepatocyte toxicity could not be predicted exclusively by electrophilic reactivity as oxidative metabolism was also a factor for toxicity.

The activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in colorectal cancer.

Abstract: Chronic ethanol consumption is associated with an increased risk for cancer of the colorectum. The highly toxic and carcinogenic compound is acetaldehyde, the product of ethanol metabolism. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH) in colorectal mucosa and bacteria. The enzyme responsible for oxidation of acetaldehyde is aldehyde dehydrogenase. The aim of this study was to compare ADH isoenzymes and ALDH activity in colorectal cancer with the activity in normal colonic mucosa. Total ADH activity was measured by a photometric method with p-nitrosodimethylaniline (NDMA) as substrate, and ALDH activity by a fluorometric method with 6-methoxy-2-naphthaldehyde as a substrate. For measurement of the activity of class I and II isoenzymes we employed fluorometric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with n-octanol as substrate, and class IV with m-nitrobenzaldehyde as substrate. Samples were taken surgically during routine operations of colorectal carcinomas from 32 patients. The activities of total ADH and, the most important in colon mucosa, class I ADH were significantly higher in cancer than in healthy tissues. The other tested classes of ADH had a tendency to higher-level activity in cancer cells than in healthy mucosa. ALDH activity was not significantly lower in the cancer cells. The activities of all tested enzymes and isoenzymes were not significantly higher in drinkers than in nondrinkers both in colorectal cancer and in normal mucosa. The differences in activities of total ADH and class I isoenzyme between cancer tissues and normal colon mucosa might be a factor for metabolic changes and disturbances in low-mature cancer cells and, additionally, might be a reason for the higher level of acetaldehyde, which can intensify carcinogenesis.

Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma.

Abstract: Despite the introduction of 13-cis-retinoic acid (13-cis-RA) into the current chemotherapy, more than half of high-risk neuroblastoma patients have experienced tumor relapses driven by chemoresistant cancer stem cells (CSCs) that can be isolated by their ability to grow as spheres. Although aldehyde dehydrogenase (ALDH) has been used to characterize CSCs in certain cancers, ALDH remains elusive in neuroblastoma. In the present study, we determined ALDH activity and expression of its 19 isoforms in spheres and parental cells of neuroblastoma. ALDH activity and several ALDH isoforms were consistently induced in spheres of different neuroblastoma cells. While ALDH1A2, ALDH1L1 and ALDH3B2 expression was consistently induced in spheres and associated with the sphere and colony formation, only ALDH1A2 expression was significantly correlated with the poor prognosis of neuroblastoma patients. ALDH1A2 expression was further associated with the growth and undifferentiation of neuroblastoma xenografts and the resistance of neuroblastoma cells to 13-cis-RA. These results suggest that ALDH1A2 is involved in the regulation of CSC properties in neuroblastoma.

Role of aldehyde oxidase in biogenic amine metabolism.

Abstract: Publisher Summary This chapter discusses the role of aldehyde oxidase in biogenic amine metabolism. It shows that both homovanillyl aldehyde and 5-hydroxy-3-indoleacetaldehyde are substrates for guinea pig liver aldehyde oxidase. The results obtained with both in vivo and in vitro inhibitors indicate that aldehyde oxidase plays a major role in homovanillic (HV) and 5-hydroxytryptamine (5-HT) metabolism in guinea pig liver. In view of the similarity between the guinea pig and human liver aldehyde oxidase, it is likely that human hepatic aldehyde oxidase may also be important in biogenic amine metabolism. The urinary metabolites of 5-HT in have been examined in oriental subjects, but no correlation was found between 5-hydroxyindoleacetic acid (5-HIAA) production and mitochondrial aldehyde dehydrogenase genotype. It was suggested that cytosolic aldehyde dehydrogenase could oxidize physiological concentrations of 5-hydroxyindoleacetaldehyde when the mitochondrial isozyme is absent. However, this oxidation could equally well be carried out by aldehyde oxidase. Although peripheral plasma levels of HV acid—the deaminated and O-methylated metabolite of dopamine—are often used as an indicator of central dopaminergic activity. Lambert have shown that HVA is produced locally, perhaps from circulating DOPA.