Quantitative analysis of mRNA expression levels of aldo-keto reductase and short-chain dehydrogenase/reductase isoforms in human livers

Amai, Keito; Fukami, Tatsuki; Ichida, Hiroyuki; Watanabe, Akïharu; Watanabe, K.; Nakajima, Miki

doi:10.1016/j.dmpk.2020.08.004

Cited by 12 publications

(17 citation statements)

References 27 publications

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“…Considering the relative protein content between cytosolic and microsomal proteins as described above (Tabata et al, 2004), the rank order of the protein level of each isoform in the human liver would be as follows: AKR1C3, AKR1C2, AKR1C4, CBR1, and HSD11B1 (AKR1C1 could not be quantified in this study). Our previous study revealed that the rank order of mRNA levels in the human liver is as follows: AKR1C2, AKR1C3, AKR1C1, CBR1, HSD11B1, and AKR1C4 (Amai et al, 2020). As AKR1C4 appears to be highly expressed at the protein level as compared to the mRNA level in the human liver, post-translational regulation may significantly contribute to its expression.…”

Section: Discussionmentioning

confidence: 99%

“…Reduced metabolites of doxorubicin are associated with cardiotoxicity induced by doxorubicin (Olson and Mushlin, 1990;Forrest et al, 2000). As there are 14-and 8-fold interindividual variabilities in AKR1C3 and CBR1 at the mRNA level (Amai et al, 2020), individuals with high expression of both isoforms would be at a high risk of developing adverse effects of doxorubicin. Loxoprofen reduction was catalyzed by rAKR1C3, rAKR1C4, and rCBR1, and their contributions to the activity in HLC were calculated to be 54%, 34%, and 31%, respectively (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the remaining contribution is likely to be AKR1C1. Although Malátková et al (2014) reported that rCBR3 can catalyze oxcarbazepine reduction, its contribution to the human liver is negligible because its expression is 230-700-fold lower than that of AKR1C1, AKR1C2, AKR1C3, AKR1C4, or CBR1 at the mRNA level (Amai et al, 2020). Malátková et al (2014) reported that in HLC, CL int of the S-licarbazepine formation was 3.7-fold higher than that of R-licarbazepine formation owing to the lower K m value, and that AKR1C1, AKR1C2, and CBR1 preferentially produced S-licarbazepine, whereas AKR1C3 and AKR1C4 mainly produced R-licarbazepine.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we evaluated the mRNA levels of 12 AKR and 6 SDR isoforms in the human liver and demonstrated that AKR1C1, AKR1C2, AKR1C3, CBR1, and HSD11B1 were expressed at over 10% of the total reductase expression, and the sum of these five isoforms reached 64.5% (Amai et al, 2020). AKR1C4 is moderately expressed (5.6% of the total reductase expression levels) (Amai et al, 2020). Early studies demonstrated that AKR1C1, AKR1C2, AKR1C3, AKR1C4, CBR1, and HSD11B1 can catalyze drug reduction reactions (Ohara et al, 1995;Matsunaga et al, 2006;Meyer et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver

et al. 2022

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Enzymes of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase superfamilies are involved in the reduction of compounds containing a ketone group. In most cases, multiple isoforms appear to be involved in the reduction of a compound, and the enzyme(s) that are responsible for the reaction in the human liver have not been elucidated.The purpose of this study was to quantitatively evaluate the contribution of each isoform to reduction reactions in the human liver. Recombinant cytosolic isoforms were constructed, i.e., AKR1C1, AKR1C2, AKR1C3, AKR1C4, and carbonyl reductase 1 (CBR1), and a microsomal isoform, 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), and their contributions to the reduction of 10 compounds were examined by extrapolating the relative expression of each reductase protein in human liver preparations to recombinant systems quantified by liquid chromatography-mass spectrometry (MS)/MS. The reductase activities for acetohexamide, doxorubicin, haloperidol, loxoprofen, naloxone, oxcarbazepine, and pentoxifylline were predominantly catalyzed by cytosolic isoforms, and the sum of the contributions of individual cytosolic reductases was almost 100%. Interestingly, AKR1C3 showed the highest contribution to acetohexamide and loxoprofen reduction, although previous studies have revealed that CBR1 mainly metabolizes them. The reductase activities of bupropion, ketoprofen, and tolperisone were catalyzed by microsomal isoform(s), and the contributions of HSD11B1 were calculated to be 41%, 32%, and 104%, respectively. To our knowledge, this is the first study to quantitatively evaluate the contribution of each reductase to the reduction of drugs in the human liver.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver

et al. 2022

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“…The AKR1B10 gene is found on chromosome 7q33, and the AKR1B10 protein is 316 amino acids long [10], [11]. AKR1B10 is implicated in detoxification, retinoic acid metabolism, and lipid synthesis, among other pathological actions.…”

Section: Introductionmentioning

confidence: 99%

Tetraprenyltoluquinone Inhibits the Tumor Marker Aldo-Keto Reductase: An in Silico Study

Hefni¹,

Dachriyanus²,

Susanti³

et al. 2022

Int. J. Adv. Sci. Eng. Inf. Technol.

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Cancer is one of the most common causes of death in the globe. The development of new cancer medicines and the identification of new therapeutic targets is still a pressing necessity. The protein AKR1B10 was discovered to be a valuable biomarker for the diagnosis and prognosis of some malignancies. Over expression of the AKR1B10 gene is found in lung cancer, oral squamous cell carcinoma, breast cancer, cholangiocarcinoma, pancreatic cancer and liver cancer. AKR1B10 is implicated in detoxification, retinoic acid metabolism, and lipid synthesis, among other pathological actions. AKR1B10 is known to be carcinogenic and can be utilized as a tumor marker, according to research. The tetraprenyltoluquinone compound is an isolate from the bark of kandis (Garcinia cowa, Roxb) which has been reported to have anticancer activity in vivo and in vitro and has the potential to be developed as an anticancer drug derived from natural ingredients. This study aims to determine the activity of the tetraprenyltoluquinone compound in silico with the target of the AKR1B10 protein. The method used is molecular docking using PLANTS (Protein Ligand ANT System) for protein visualization and preparation and Ligplus program for visualizing amino acids. The docking score results showed that the AKR1B10 protein interaction with the test ligand tetraprenyltoluquinone is lower than the native ligand, which means the binding energy of tetraprenyltoluquinone to the AKR1B10 (PDB ID: 1ZUA) protein was higher than the native ligand tolrestat. These results indicate that tetraprenyltoluquinone is a potential inhibitor of the AKR1B10 protein in the pathway of cancer.

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Identification of HSD17B12 as an enzyme catalyzing drug reduction reactions through investigation of nabumetone metabolism

Ichida¹,

Fukami²,

Kudo³

et al. 2023

Archives of Biochemistry and Biophysics

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Quantitative analysis of mRNA expression levels of aldo-keto reductase and short-chain dehydrogenase/reductase isoforms in human livers

Cited by 12 publications

References 27 publications

Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver

Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver

Tetraprenyltoluquinone Inhibits the Tumor Marker Aldo-Keto Reductase: An in Silico Study

Identification of HSD17B12 as an enzyme catalyzing drug reduction reactions through investigation of nabumetone metabolism

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