Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D2, and other endogenous and xenobiotic carbonyl compounds

Cloning and Characterization of Four Rabbit Aldo-Keto Reductases Featuring Broad Substrate Specificity for Xenobiotic and Endogenous Carbonyl Compounds: Relationship with Multiple Forms of Drug Ketone Reductases

“…AKR1C33 is the first mammalian enzyme that reduces fenofibric acid, suggesting that enzymes in the AKR1C subfamily may be responsible for the pharmacologically significant reduction of this drug in other mammalian species. In addition to the differences in reactivity toward the above drug ketones, the present four AKRs differ from one another and AKR1C29 (Endo et al, 2013c) in their kinetic constants for other xenobiotic carbonyl compounds. Thus, one reason for the existence of the five NADPH-dependent AKR1C subfamily enzymes in many rabbit tissues is the elimination of structurally divergent xenobiotic carbonyl compounds by their metabolism into the corresponding less lipophilic alcohols, which are excreted directly or after conjugation by phase II drug-metabolizing enzymes.…”

“…These study results revealed that in addition to AKR1C29 (Endo et al, 2013c), four AKRs (AKR1C30, AKR1C31, AKR1C32, and AKR1C33) with broad substrate specificity are distributed in many rabbit tissues. The differences between the enzymes in their substrate specificity for drug ketones suggest that their relationship with the following multiple forms of NADPH-dependent drug ketone reductases that were separated or isolated from rabbit liver cytosol.…”

“…2) LRs: AKR1C32 is also identical to the major form of rabbit liver LR (Tanaka et al, 1984), because its substrate specificity for 3-keto-5a/b-androstanes, 5b-androstan-3a-ol-17-one, and adamantanone resembles that of this form of LR. Although the other three multiple forms of rabbit liver LR were not characterized, they may correspond to AKR1C31, AKR1C29, and (Imamura et al, 1989;Endo et al, 2013c). 3) Reductases for befunolol and daunorubicin: although CBR and/or aldehyde reductase are the major forms of the two drug reductases for befunolol and daunorubicin, further multiple forms distinct from the two enzymes were separated from rabbit liver cytosol (Ahmed et al, 1978(Ahmed et al, , 1979Felsted et al, 1980;Imamura et al, 1989).…”

“…AKR1C5 reduces xenobiotic carbonyl compounds including befunolol and ketotifen, although it is expressed specifically in the rabbit ovary and uterus (Endo et al, 2013a). AKR1C29 ubiquitously expressed in rabbit tissues reduces befunolol, daunorubicin, naloxone, and loxoprofen, as well as endogenous substrates such as 3-, 17-, and 20-ketosteroids and PGD 2 (Endo et al, 2013c). However, the properties and/or amino acid sequences of AKR1C5 and AKR1C29 are different from those of NR1 and NR2 and the major form of LR.…”

Probing AKR1C30 and AKR1C31 with Site-Directed Mutagenesis: Identifying the Roles of Residues 54 and 56 in the Binding of Substrates and Inhibitors

“…3,[5][6][7][8][9][10] In rabbits, such AKRs are six, which are AKR1C5 acting as 17β/20α-HSD, 11,12) AKR1C29 (that is identical to 3-hydroxyhexobarbital dehydrogenase and exhibits 3α/3β/17β/20α-HSD activity), 13) AKR1C30 (that is identical to naloxone reductase type 1 and acts as 17β-HSD), AKR1C31 (that acts as 3α/17β/20α-HSD), AKR1C32 (that is identical to loxoprofen reductase and acts as 3α/20α-HSD) and AKR1C33 (that is identical to naloxone reductase type 2 and mainly acts as 3α-HSD).…”