Characterization of a novel variant (S145C/L311V) of 3 ??-hydroxysteroid/dihydrodiol dehydrogenase in human liver

Kume,; Toshiyuki,; Iwasa,; Harunori,; Shiraishi,; Hiroaki,; Yokoi,; Tsuyoshi,; Nagashima,; Kazuo,; Otsuka,; Mineo,; Terada,; Tomoyuki,; Takagi, Toshiyuki; Tetsuya,; Hara,; Akira,; Kamataki,

doi:10.1097/01213011-199912000-00011

Cited by 9 publications

(15 citation statements)

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“…V MAX values for EXE reduction did not appreciably differ (6.3 ± 0.8 and 2.3 ± 0.6 pmol·min −1 ·mg −1 ), which is consistent with a previous study concluding that overall catalytic activity of the Ser145Cys variant is comparable to wildtype AKR1C4 using several test substrates [50]. …”

Section: Discussionsupporting

confidence: 91%

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

Platt

Xia

Liu

et al. 2016

Pharmacogenetics and Genomics

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Objective Exemestane is a potent third-generation aromatase inhibitor used as endocrine therapy in breast cancer treatment and prevention. Characterization of its metabolic pathway is incomplete with ambiguity existing in the identity of enzymes driving production of its key metabolite, 17β-dihydroexemestane. The impact of genetic variation on exemestane metabolism is also unknown. This study seeks to describe cytosolic reductase involvement in hepatic exemestane metabolism and to assess the impact of functional polymorphisms on metabolite production. Methods Phase I metabolites were identified in incubations of exemestane with pooled human liver cytosol or recombinant protein for AKR1Cs and CBR1. Kinetic parameters characterizing exemestane reduction were measured for purified wildtype enzymes, and nonsynonymous variants occurring at >1% minor allele frequency using UPLC/MS/MS. Results Human liver cytosol, CBR1, AKR1C1, AKR1C2, AKR1C3, and AKR1C4 reduce exemestane to active primary metabolite 17β-dihydroexemestane. Formation of a novel metabolite, 17α-dihydroexemestane, was catalyzed by recombinant AKR1C4 and CBR1 in addition to hepatic cytosol. Variants AKR1C3 Arg258Cys and AKR1C4 Gly135Glu had significantly decreased affinity for EXE relative to their respective wildtypes. Five common AKR1C3 polymorphisms were associated with decreased rates of catalysis while AKR1C4 Gly135Glu increased the velocity of EXE reduction. Conclusions AKR1Cs and CBR1 catalyze exemestane reduction in vitro. These results imply that cytosolic ketosteroid reductases may participate in the exemestane metabolic pathway in vivo. In addition, several common variants were associated with altered enzymatic activity, suggesting that functional polymorphisms could play an important role in overall exemestane metabolism and activity by altering the extent and duration of 17β-dihydroexemestane exposure.

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Section: Discussionsupporting

confidence: 91%

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

Platt

Xia

Liu

et al. 2016

Pharmacogenetics and Genomics

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“…16,32 Such variability has been associated with a protein variant that arises from two nucleotide (C to G) substitutions at positions 434 and 931 of the cDNA. 32 We show here that these two mutations are in complete linkage disequilibrium and that the frequency of the variant allele (0.04) is lower than that previously reported in whites (0.10). 33 Although limited by the small number of subjects, the observed high risk associated with carrying at least one variant allele, for individuals with chlordecone concentrations above the LD, is consistent with the mutated enzyme being less efficient.…”

Section: ‫ء‬contrasting

confidence: 76%

Chlordecone Exposure and Risk of Prostate Cancer

Multigner

Ndong

Giusti

et al. 2010

JCO

287

178

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“…Polymorphisms in the 11b-hydroxysteroid dehydrogenase gene have been associated with hypertension and obesity (Draper et al, 2002;Gelernter-Yaniv et al, 2003;Stewart, 1996). Additional information about genetic polymorphisms or interindividual differences in human carbonyl-reducing enzymes may be found in Iwata et al (1993); Kume et al (1999); Rady-Pentek et al (1997); Shiraishi et al (1998); Winters et al (1990).…”

Section: Carbonyl Reduction and Drug Interactionsmentioning

confidence: 94%

Human Carbonyl Reduction Pathways and a Strategy for Their Study In Vitro

Rosemond¹,

Walsh²

2004

Drug Metabolism Reviews

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Carbonyl reduction plays a significant role in physiological processes throughout the body. Although much is known about endogenous carbonyl metabolism, much less is known about the roles of carbonyl-reducing enzymes in xenobiotic metabolism. Multiple pathways exist in humans for metabolizing carbonyl moieties of xenobiotics to their corresponding alcohols, readying these molecules for subsequent conjugation and/or excretion. When exploring carbonyl reduction clearance pathways for a drug development candidate, it is possible to assess the relative contributions of these enzymes due to their differences in subcellular locations, cofactor dependence, and inhibitor profiles. In addition, the contributions of these enzymes may be explored by varying incubation conditions, such as pH. Presently, individual isoforms of carbonyl-reducing enzymes are not widely available, either in recombinant or purified form. However, it is possible to study carbonyl reduction clearance pathways from simple experiments with commercially available reagents. This article provides an overview of carbonyl-reducing enzymes, including some kinetic data for substrates and inhibitors. In addition, an experimental strategy for the study of these enzymes in vitro is presented.

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Characterization of a novel variant (S145C/L311V) of 3 ??-hydroxysteroid/dihydrodiol dehydrogenase in human liver

Cited by 9 publications

References 0 publications

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

Impact of nonsynonymous single nucleotide polymorphisms on in-vitro metabolism of exemestane by hepatic cytosolic reductases

Chlordecone Exposure and Risk of Prostate Cancer

Human Carbonyl Reduction Pathways and a Strategy for Their Study In Vitro

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