Evolution of a Major Drug Metabolizing Enzyme Defect in the Domestic Cat and Other Felidae: Phylogenetic Timing and the Role of Hypercarnivory

1. Adjuvant-induced arthritis in rats is accompanied by a loss of activity of the drug-metabolizing enzyme system and a decrease in hepatic cytochrome P-450. 2. Arthritic rats have normal serum and liver cholesterol concentrations. 3. The rate of biogenesis of cholesterol in vivo and in vitro from either [14C]acetate or [14C]mevalonate in arthritic rats was the same as or greater than that found in control rats. 4. Treatment of rats with carbon disulphide (1ml/kg) resulted in a loss of drug-metabolizing-enzyme activity and increased cholesterol biogenesis. 5. The activity of cholesterol 7α-hydroxylase in adjuvant-induced arthritic rats did not differ significantly from that in control rats. 6. Rats fed with cholestyramine had an elevated hepatic cholesterol 7α-hydroxylase activity, but neither the concentration of cytochrome P-450 nor the activity of the drug-hydroxylating enzyme, aminopyrine demethylase, was affected. 7. The relationships between drug hydroxylation and cholesterol metabolism are discussed.

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Carbon tetrachloride-induced changes in the activity of phase II drug-metabolizing enzyme in the liver of male rats: role of antioxidants

Toxicology ◽

10.1016/s0300-483x(01)00429-2 ◽

2001 ◽

Vol 165 (2-3) ◽

pp. 217-224 ◽

Cited By ~ 71

Author(s):

S.A Sheweita ◽

M Abd El-Gabar ◽

M Bastawy

Keyword(s):

Carbon Tetrachloride ◽

Phase Ii ◽

Male Rats ◽

Drug Metabolizing Enzyme ◽

Metabolizing Enzyme ◽

Induced Changes

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Role of Adaptor Protein Toll-Like Interleukin Domain Containing Adaptor Inducing Interferon in Toll-Like Receptor 3- and 4-Mediated Regulation of Hepatic Drug Metabolizing Enzyme and Transporter Genes

Drug Metabolism and Disposition ◽

10.1124/dmd.115.066761 ◽

2015 ◽

Vol 44 (1) ◽

pp. 61-67 ◽

Cited By ~ 7

Author(s):

P. Shah ◽

O. Omoluabi ◽

B. Moorthy ◽

R. Ghose

Keyword(s):

Adaptor Protein ◽

Toll Like Receptor ◽

Hepatic Drug ◽

Drug Metabolizing Enzyme ◽

Metabolizing Enzyme

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Control of δ-aminolaevulinate synthase and haem oxygenase in chroniciron-overloaded rats

Biochemical Journal ◽

10.1042/bj2000035 ◽

1981 ◽

Vol 200 (1) ◽

pp. 35-42 ◽

Cited By ~ 21

Author(s):

N G Ibrahim ◽

J C Nelson ◽

R D Levere

Keyword(s):

Iron Overload ◽

Inborn Errors ◽

Cellular Iron ◽

Drug Metabolizing Enzyme ◽

Oxygenase Activity ◽

Exogenous Agents ◽

Haem Oxygenase ◽

Metabolizing Enzyme ◽

Cytochrome P 450

The hepatic porphyrias are inborn errors of porphyrin and haem biosynthesis characterized biochemically by excessive excretion of delta-aminolaevulinate (ALA), porphobilinogen and other intermediates in haem synthesis. Clinical evidence has implicated iron in the pathogenesis of several types of genetically transmitted diseases. We investigated the role of iron in haem metabolism as well as its relationship to drug-mediated induction of ALA synthase and haem oxygenase in acute and chronic iron overload. Acute iron overload in rats resulted in a marked increase in hepatic haem oxygenase that was associated with a decrease in cytochrome P-450 and an increase in ALA synthase activity. Aminopyrine N-demethylase and aniline hydroxylase activities, which are dependent on the concentration of cytochrome P-450, were also decreased. In contrast, in chronic-iron-overloaded rats, there was an adaptive increase in haem oxygenase activity and an increase in ALA synthase that was associated with normal concentrations of microsomal haem and cytochrome P-450. The induction of ALA synthase in chronic iron overload was enhanced by phenobarbital and allylisopropylacetamide, in spite of the fact that these agents did not increase haem oxygenase activity. Small doses of Co2+ were potent inducers of the haem oxygenase in chronic-iron-overloaded, but not in control, animals. We conclude that increased hepatic cellular iron may predispose certain enzymes of haem synthesis to induction by exogenous agents and thereby affect drug-metabolizing enzyme activities.

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Enzymatically Produced Trimethylamine N-Oxide: Conserving It or Eliminating It

Catalysts ◽

10.3390/catal9121028 ◽

2019 ◽

Vol 9 (12) ◽

pp. 1028 ◽

Cited By ~ 3

Author(s):

Gianluca Catucci ◽

Giulia Querio ◽

Sheila J. Sadeghi ◽

Gianfranco Gilardi ◽

Renzo Levi

Keyword(s):

Marine Mammals ◽

Hydrostatic Stress ◽

Physiological Role ◽

Health Conditions ◽

Renal Diseases ◽

Drug Metabolizing Enzyme ◽

Long Time ◽

Metabolizing Enzyme ◽

Very High

Trimethylamine N-Oxide (TMAO) is the product of the monooxygenation reaction catalyzed by a drug-metabolizing enzyme, human flavin-containing monooxygenase 3 (hFMO3), and its animal orthologues. For several years, researchers have looked at TMAO and hFMO3 as two distinct molecules playing specific but separate roles, the former to defend saltwater animals from osmotic or hydrostatic stress and the latter to process xenobiotics in men. The presence of high levels of plasmatic TMAO in elasmobranchs and other animals was demonstrated a long time ago, whereas the actual physiological role of hFMO3 is still unknown because the enzyme has been mainly characterized for its ability to oxidize drugs. Recently TMAO was found to be related to several human health conditions such as atherosclerosis, cardiovascular, and renal diseases. This correlation poses a striking question of how other vertebrates (and invertebrates) can survive in the presence of very high TMAO concentrations (micromolar in humans, millimolar in marine mammals and several hundred millimolar in elasmobranchs). Therefore, it is important to address how TMAO, its precursors, and FMO catalytic activity are interconnected.

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The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression

Pharmacology & Therapeutics ◽

10.1016/j.pharmthera.2006.07.004 ◽

2007 ◽

Vol 113 (1) ◽

pp. 88-120 ◽

Cited By ~ 111

Author(s):

Sang K. Kim ◽

Raymond F. Novak

Keyword(s):

Protein Expression ◽

Intracellular Signaling ◽

Enzyme Gene ◽

Drug Metabolizing Enzyme ◽

Gene And Protein Expression ◽

Metabolizing Enzyme

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Role of the Drug-Metabolizing Enzyme CYP during Mouse Liver Development

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b16-00479 ◽

2016 ◽

Vol 39 (12) ◽

pp. 2015-2021 ◽

Cited By ~ 1

Author(s):

Wataru Ochiai ◽

Akiyo Hirose ◽

Taisuke Kawamura ◽

Kyoko Komachi ◽

Yuka Yamamoto ◽

...

Keyword(s):

Mouse Liver ◽

Liver Development ◽

Drug Metabolizing Enzyme ◽

Metabolizing Enzyme

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The crystal structure of human Aldehyde Oxidase in native and inhibited forms

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314081728 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C1828-C1828

Author(s):

Catarina Coelho ◽

Tobias Hartmann ◽

Alessandro Foti ◽

Teresa Santos-Silva ◽

Silke Leimkühler ◽

...

Keyword(s):

Active Site ◽

3D Structure ◽

Aldehyde Oxidase ◽

Drug Metabolizing Enzyme ◽

Resolution Analysis ◽

Metabolizing Enzyme ◽

Novel Drug ◽

First Time ◽

Important Drug

Aldehyde oxidases (AOX; E.C. 1.2.3.1) are molybdo-flavoenzymes with broad substrate specificity, oxidizing aldehydes and N-heterocycles. AOX belongs to the xanthine oxidase (XO) family of Mo-containing enzymes. The true physiological function of AOX is still unknown, although it is recognized to play a role in the metabolism of compounds with medicinal and toxicological relevance [1]. AOX importance has increased in recent years since it is substituting Cyt-P450 as the central drug-metabolizing system in humans. We have solved the 3D structure of mouse AOX3 to 2.9 Å resolution [2] that was the first structure of an aldehyde oxidase, providing important evidences on substrate and inhibitor specificities between AOX and XO. The complement of AOX proteins in mammals varies from one in humans (hAOX1) to four in rodents (mAOX1, mAOX3, mAOX4 and mAOX3L1) as a result of evolutionary genetic events. Due to this unusual complement of AOX genes in different animal species, conclusions regarding protein metabolism in humans cannot be taken exclusively from the mouse model. Using the human aldehyde oxidase (hAOX1) purified after heterologous expression in Escherichia coli we were able to crystallize it and solve its 3D structure to 2.7 Å resolution (submitted). In addition to the native protein we also solved the structure of an inhibited form of the enzyme to 2.6Å resolution. Analysis of the protein active site and comparison with the structure of the mouse isoform (mAOX3) allowed us to identity, for the first time, the unique features that characterize hAOX1 as an important drug-metabolizing enzyme. In spite of the similarities of both enzymes, they show marked and relevant differences at the Mo active site, substrate tunnel as well as at the FAD site. The ensemble of these structures provides important insights into the role of aldehyde oxidases, contributing to elucidate the clinical metabolism implications of hAOX1 in humans which has particular relevance for novel drug design studies.

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