Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members

Abstract

Complementary DNA clones encoding human aflatoxin B(1) aldehyde reductase (AKR7A2), aldehyde reductase (AKR1A1), aldose reductase (AKR1B1), dihydrodiol dehydrogenase 1 (AKR1C1) and chlordecone reductase (AKR1C4) have been expressed in Escherichia coli. These members of the aldo-keto reductase (AKR) superfamily have been purified from E. coli as recombinant proteins. The recently identified AKR7A2 was shown to differ from the AKR1 isoenzymes in being able to catalyse the reduction of 2-carboxybenzaldehyde. Also, AKR7A2 was found to exhibit a narrow substrate specificity, with activity being restricted to succinic semialdehyde (SSA), 2-nitrobenzaldehyde, pyridine-2-aldehyde, isatin, 1,2-naphthoquinone (1,2-NQ) and 9,10-phenanthrenequinone. In contrast, AKR1A1 reduces a broad spectrum of carbonyl-containing compounds, displaying highest specific activity for SSA, 4-carboxybenzaldehyde, 4-nitrobenzaldehyde, pyridine-3-aldehyde, pyridine-4-aldehyde, 4-hydroxynonenal, phenylglyoxal, methylglyoxal, 2,3-hexanedione, 1, 2-NQ, 16-ketoestrone and d-glucuronic acid. Comparison between the kinetic properties of AKR7A2 and AKR1A1 showed that both recombinant enzymes exhibited roughly similar k(cat)/K(m) values for SSA, 1,2-NQ and 16-ketoestrone. Many of the compounds which are substrates for AKR1A1 also serve as substrates for AKR1B1, though the latter enzyme was shown to display a specific activity significantly less than that of AKR1A1 for most of the aromatic and aliphatic aldehydes studied. Neither AKR1C1 nor AKR1C4 was found to possess high reductase activity towards aliphatic aldehydes, aromatic aldehydes, aldoses or dicarbonyls. However, unlike AKR1A1 and AKR1B1, both AKR1C1 and AKR1C4 were able to catalyse the oxidation of 1-acenaphthenol and, in addition, AKR1C4 could oxidize di- and tri-hydroxylated bile acids. Specific antibodies raised against AKR7A2, AKR1A1, AKR1B1, AKR1C1 and AKR1C4 have been used to show the presence of all of the reductases in human hepatic cytosol; the levels of AKR1B1 and AKR1C1 were markedly elevated in livers with alcohol-associated injury, and indeed AKR1B1 was only detectable in livers with evidence of alcoholic liver disease. Western blotting of extracts from brain, heart, kidney, liver, lung, prostate, skeletal muscle, small intestine, spleen and testis showed that AKR7A2 is present in all of the organs examined, and AKR1B1 is similarly widely distributed in human tissues. These experiments revealed however, that the expression of AKR1A1 is restricted primarily to brain, kidney, liver and small intestine. The AKR1C family members proved not to be as widely expressed as the other reductases, with AKR1C1 being observed in only kidney, liver and testis, and AKR1C4 being found in liver alone. As human kidney is a rich source of AKR, the isoenzymes in this organ have been studied further. Anion-exchange chromatography of human renal cytosol on Q-Sepharose allowed resolution of AKR1A1, AKR1B1, AKR1C1 and AKR7A2, as identified by substrate specificity and Western blotting. Immunohistochemistry...

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines

“…AKR1B1, AKR1B10 and the AKR1C isoforms 1 through 4 have been shown to be primarily expressed in the liver, with AKR1C4 being exclusively expressed in this organ. While most studies focus on the AKR1 family of enzymes and their ability to metabolize anthracyclines, it should be noted that AKR7A2 has also been shown to have some metabolic activity towards these substances in a wide variety of organs [52]. While belonging to a different family of enzymes, this ability of AKR7A2 demonstrates the potential that other AKR family members may play yet undiscovered roles in anthracycline metabolism.…”

“…There is less support for the role of AKRs in promoting the cardiotoxicity of anthracyclines. For example, DOX is considered to have the greatest effect on cardiotoxicity; however, it has the lowest affinity for AKR enzymes [48], in particular for AKR7A2, which has been shown to have very low specific activities towards DOX and DNR [52]. In contrast, IDA, which has one of the lowest cardiotoxicities of the anthracyclines has one of the highest affinities for metabolism by AKR’s [48].…”

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

“…In humans, there are 15 different AKRs that play key roles in the metabolism of sugar and lipid aldehydes, e.g., advanced glycation end products 14,15 and 4-hydroxy-2-nonenal (4-HNE), respectively; 8,16 chemical carcinogens, e.g., aflatoxin dialdehyde; 17 polycyclic aromatic trans -dihydrodiols; 18,19 nicotine-derived nitrosaminoketones (NNK); 20,21 as well as cancer chemotherapeutic agents. 22–25 The human AKR genes are involved in the metabolism of prostaglandins 26–29 and natural and synthetic steroid hormones, 30–34 all of which contain carbonyl functionalities (Table 1).…”

Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome

“…In spite of the prominent contributions of CBRs and AKRs towards the pharmacodynamics of anthracycline drugs, reports documenting gene expression levels and protein abundance in cardiac tissue are limited to the analysis of individual samples or pooled tissue samples (13, 22, 23). Thus, the main goal of this study was to document the extent of interindividual variability in the expression of CBR1, CBR3, AKR1A1, AKR1C3 and AKR7A2 in a collection of heart samples from donors with- and without- DS.…”