Dehydrogenation of Indanol by Rabbit Liver 3-Hydroxyhexobarbital Dehydrogenase

Takenoshita, Reiko; Toki, Satoshi

doi:10.3109/00498257709035797

Cited by 7 publications

(2 citation statements)

References 5 publications

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“…Those enzymes which have been examined are generally from liver or bacterial sources, rather than classical endocrine or endocrine responsive tissues. Examples of HSDs known to use non-steroidal compounds as substrates include Pseudomonas testosteroni 3a-HSD (Mukharji, 1982;Ringold et al, 1967a,b), Pseudomonas testosteroni 3,-HSD (Ringold, 1967b), Streptomyces hydrogenans 3a,20,-HSD (White & Jeffery, 1977), 3a-HSD of rat liver cytosol (Penning et al, 1984) and 17,8-HSD of rabbit, guinea-pig and mouse liver (Takenoshita & Toki, 1977;Hara et al, 1985Hara et al, , 1986Swada et al, 1988). In other studies, compounds containing a partial steroid nucleus have been shown to be substrates of placental 17,/-HSD, including methoxy-3-A-des-oestradiol (Boussioux et al, 1973).…”

Section: Discussionmentioning

confidence: 99%

Synthesis and evaluation of non-steroidal mechanism-based inactivators of 3α-hydroxysteroid dehydrogenase

Ricigliano

Penning

1989

Biochemical Journal

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Two non-steroidal mechanism-based inactivators for 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) of rat liver have been synthesized: 1-(4'-nitrophenyl)-2-propen-1-ol (I), and 1-(4'-nitrophenyl)-2-propyn-1-ol (II). Both of these compounds inactivate homogeneous 3 alpha-HSD in a time- and concentration-dependent manner only in the presence of NAD+. Analysis of the pseudo-first-order inactivation data gave a Kd of 1.2 mM for the allylic alcohol and a t1/2 (time required to promote a 50% loss of enzyme activity) for the enzyme of less than 10 s at saturation. Similar inactivation studies with the acetylenic alcohol gave a Kd of 1.5 mM and a t1/2 for the enzyme of 9.9 min at saturation. The allylic alcohol and acetylenic alcohol are oxidized stereoselectively by the enzyme, yielding a Km of 2.0 mM and a Vmax. of 0.58 mumol/min per mg for the allylic alcohol and a Km of 0.75 mM and a Vmax. of 0.29 mumol/min per mg for the acetylenic alcohol. Effective partition ratios (kcat./kinact.) are low for both alcohols: for the allylic alcohol, 5.3; and for the acetylenic alcohol, 141. H.p.l.c. indicates that the Michael acceptors 1-(4'-nitrophenyl)-2-propen-1-one (III) and 1-(4'-nitrophenyl-2-propyn-1-one (IV) are the products of the enzymic oxidation of the corresponding alcohols. The latter compound (IV) was trapped as its monothioether adducts before h.p.l.c. analysis. The Michael acceptors III and IV inactivate the 3 alpha-HSD in the absence of NAD+ at a rate too high to accurately measure and titrate the enzyme in a stoichiometric manner. Enzyme inactivated by I and NAD+, II and NAD+, III or IV is not re-activated by gel filtration or dialysis, implying a stable covalent bond has been formed between the enzyme and the inactivators. A screen of five other HSDs, and two aliphatic alcohol dehydrogenases, indicates that alcohol I is a selective inactivator of rat liver 3 alpha-HSD. It is concluded that 3 alpha-HSD generates non-steroidal alkylating agents (III and IV) that potently inactivate the enzyme with low effective partition coefficients. This report of non-steroidal mechanism-based inactivators of 3 alpha-HSD may provide a precedent for the development of related compounds to act as suicide substrates of other HSDs.

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Section: Discussionmentioning

confidence: 99%

Synthesis and evaluation of non-steroidal mechanism-based inactivators of 3α-hydroxysteroid dehydrogenase

Ricigliano

Penning

1989

Biochemical Journal

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“…For OH-HB, CL R was l4.2±2.6 ml.min r l.kg " ', and for K-HB 13.8 ± 2.5 ml.min r l.kg " '. bit liver 3'-hydroxyhexobarbitaldehydrogenase can convert certain alcohols to ketones and vice versa (5,12).…”

Section: Renal Clearancementioning

confidence: 99%

Disposition of allylic oxidation pathway metabolites of racemic hexobarbital in the rat

Graaff

Vermeulen

Vinks

et al. 1986

European Journal of Drug Metabolism and Pharmacokinetics

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The pharmacokinetics in blood of the major metabolites of hexobarbital (HB), 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) were studied in rats. In addition urinary excretion of OH-HB and K-HB and 1,5-dimethylbarbituric acid (DMBA) was determined. Half-lives of OH-HB and K-HB were slightly longer than that of the parent drug. Urinary recovery of OH-HB, K-HB and DMBA following i.a. administration of OH-HB (75%) was more complete than the recovery following i.a. administration of K-HB (52%). Most probably further metabolism of K-HB takes place. Of K-HB, 41% was excreted renally, and 3.4% of K-HB reverted back to OH-HB. Of OH-HB, about 45% was excreted renally, following p.o. or i.a. administration. Since about 10% of both OH-HB and K-HB was converted to DMBA, it seems that the epoxide-diol pathway as proposed for HB also plays a minor role in the metabolism of OH-HB and K-HB. It is further concluded that measuring allylic pathway oxidation metabolites of HB does not improve the usefulness of HB as a model compound in the assessment of the activity of oxidative drug metabolizing activity.

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

Endo

Matsunaga

Matsumoto

et al. 2013

Biochemical Pharmacology

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Dehydrogenation of Indanol by Rabbit Liver 3-Hydroxyhexobarbital Dehydrogenase

Cited by 7 publications

References 5 publications

Synthesis and evaluation of non-steroidal mechanism-based inactivators of 3α-hydroxysteroid dehydrogenase

Synthesis and evaluation of non-steroidal mechanism-based inactivators of 3α-hydroxysteroid dehydrogenase

Disposition of allylic oxidation pathway metabolites of racemic hexobarbital in the rat

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

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