-
British Journal of Pharmacology May 2016Hydrogen sulfide (H2S) is a gasotransmitter produced from L-cysteine through the enzymatic action of cystathionine-γ-lyase (CSE) and/or cystathionine-β-synthase....
BACKGROUND AND PURPOSE
Hydrogen sulfide (H2S) is a gasotransmitter produced from L-cysteine through the enzymatic action of cystathionine-γ-lyase (CSE) and/or cystathionine-β-synthase. D-Penicillamine is the d isomer of a dimethylated cysteine and has been used for the treatment of rheumatoid arthritis. AsD-penicillamine is structurally very similar to cysteine, we have investigated whether D-penicillamine, as a cysteine analogue, has an effect on the H2 S pathway.
EXPERIMENTAL APPROACH
We tested the effect of D-penicillamine (0.01-1 mM) in mouse aortic rings mounted in isolated organ baths and determined whether it could affect H2 S biosynthesis. In particular, we investigated any possible inhibitor or donor behaviour by using recombinant enzyme-based assays and an in vivo approach.
KEY RESULTS
D-Penicillamine, per se, showed little or no vasodilator effect, and it cannot be metabolized as a substrate in place of l-cysteine. However, d-penicillamine significantly reduced L-cysteine-induced vasodilatation in a concentration-dependent manner through inhibition of H2 S biosynthesis, and this effect occurred at concentrations 10 times lower than those needed to induce the release of H2 S. In particular, D-penicillamine selectively inhibited CSE in a pyridoxal-5'-phosphate-dependent manner.
CONCLUSIONS AND IMPLICATIONS
Taken together, our results suggest that D-penicillamine acts as a selective CSE inhibitor, leading to new perspectives in the design and use of specific pharmacological tools for H2 S research. In addition, the inhibitory effect of D-penicillamine on CSE could account for its beneficial action in rheumatoid arthritis patients, where H2 S has been shown to have a detrimental effect.
Topics: Animals; Cystathionine gamma-Lyase; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hydrogen Sulfide; Male; Mice; Penicillamine; Signal Transduction; Structure-Activity Relationship
PubMed: 26890936
DOI: 10.1111/bph.13459 -
British Medical Journal Jun 1979
Topics: Arthritis, Rheumatoid; Female; Humans; Middle Aged; Myotonia; Neuromuscular Diseases; Penicillamine
PubMed: 466063
DOI: 10.1136/bmj.1.6176.1464 -
Journal of the Royal Society of Medicine May 1981
Topics: Arthritis, Rheumatoid; Humans; Male; Middle Aged; Myositis; Penicillamine
PubMed: 7241487
DOI: No ID Found -
Proceedings of the Royal Society of... 1977
Review
Topics: Arthritis, Juvenile; Arthritis, Rheumatoid; Humans; Penicillamine; Wound Healing
PubMed: 122679
DOI: No ID Found -
Basic & Clinical Pharmacology &... May 2012Previous studies on animals have revealed that garlic (Allium sativum) is effective in reducing blood and tissue lead concentrations. The aim of this study was to... (Comparative Study)
Comparative Study Randomized Controlled Trial
Previous studies on animals have revealed that garlic (Allium sativum) is effective in reducing blood and tissue lead concentrations. The aim of this study was to investigate therapeutic effects of garlic and compare it with d-penicillamine in patients with chronic lead poisoning. After coordination and obtaining informed consent, clinical examinations and blood lead concentration (BLC) of 117 workers at a car battery industry were investigated. BLC was determined by heated graphite atomization technique of an atomic absorption spectrometer. The workers were randomly assigned into two groups of garlic (1200 μg allicin, three times daily) and d-penicillamine (250 mg, three times daily) and treated for 4 weeks. BLC was determined again 10days post-treatment. Clinical signs and symptoms of lead poisoning were also investigated and compared with the initial findings. Clinical improvement was significant in a number of clinical manifestations including irritability (p = 0.031), headache (p = 0.028), decreased deep tendon reflex (p=0.019) and mean systolic blood pressure (0.021) after treatment with garlic, but not d-penicillamine. BLCs were reduced significantly (p=0.002 and p=0.025) from 426.32±185.128 to 347.34±121.056 μg/L and from 417.47±192.54 to 315.76±140.00μg/L in the garlic and d-penicillamine groups, respectively, with no significant difference (p=0.892) between the two groups. The frequency of side effects was significantly (p=0.023) higher in d-penicillamine than in the garlic group. Thus, garlic seems safer clinically and as effective as d-penicillamine. Therefore, garlic can be recommended for the treatment of mild-to-moderate lead poisoning.
Topics: Adult; Antioxidants; Chelating Agents; Chronic Disease; Double-Blind Method; Female; Garlic; Humans; Lead Poisoning; Male; Middle Aged; Occupational Diseases; Occupational Exposure; Penicillamine; Plant Extracts; Prospective Studies
PubMed: 22151785
DOI: 10.1111/j.1742-7843.2011.00841.x -
Inorganic Chemistry Apr 2013The complex formation between silver(I) and cysteine (H2Cys), penicillamine (H2Pen), and glutathione (H3Glu) in alkaline aqueous solution was examined using extended...
The complex formation between silver(I) and cysteine (H2Cys), penicillamine (H2Pen), and glutathione (H3Glu) in alkaline aqueous solution was examined using extended X-ray absorption fine structure (EXAFS) and (109)Ag NMR spectroscopic techniques. The complexes formed in 0.1 mol dm(-3) Ag(I) solutions with cysteine and penicillamine were investigated for ligand/Ag(I) (L/Ag) mole ratios increasing from 2.0 to 10.0. For the series of cysteine solutions (pH 10-11) a mean Ag-S bond distance of 2.45 ± 0.02 Å consistently emerged, while for penicillamine (pH 9) the average Ag-S bond distance gradually increased from 2.40 to 2.44 ± 0.02 Å. EXAFS and (109)Ag NMR spectra of a concentrated Ag(I)-cysteine solution (C(Ag(I)) = 0.8 mol dm(-3), L/Ag = 2.2) showed a mean Ag-S bond distance of 2.47 ± 0.02 Å and δ((109)Ag) 1103 ppm, consistent with prevailing, partially oligomeric AgS3 coordinated species, while for penicillamine (C(Ag(I)) = 0.5 mol dm(-3), L/Ag = 2.0) the mean Ag-S bond distance of 2.40 ± 0.02 Å and δ((109)Ag) 922 ppm indicate that mononuclear AgS2 coordinated complexes dominate. For Ag(I)-glutathione solutions (C(Ag(I)) = 0.01 mol dm(-3), pH ∼11), mononuclear AgS2 coordinated species with a mean Ag-S bond distance of 2.36 ± 0.02 Å dominate for L/Ag mole ratios from 2.0 to 10.0. The crystal structure of the silver(I)-cysteine compound (NH4)Ag2(HCys)(Cys)·H2O (1) precipitating at pH ∼10 was solved and showed a layer structure with both AgS3 and AgS3N coordination to the cysteinate ligands. A redetermination of the crystal structure of Ag(HPen)·H2O (2) confirmed the proposed digonal AgS2 coordination environment to bridging thiolate sulfur atoms in polymeric intertwining chains forming a double helix. A survey of Ag-S bond distances for crystalline Ag(I) complexes with S-donor ligands in different AgS2, AgS2(O/N), and AgS3 coordination environments was used, together with a survey of (109)Ag NMR chemical shifts, to assist assignments of the Ag(I) coordination in solution.
Topics: Coordination Complexes; Cysteine; Glutathione; Magnetic Resonance Spectroscopy; Models, Molecular; Penicillamine; Silver; X-Ray Absorption Spectroscopy
PubMed: 23556419
DOI: 10.1021/ic400192c -
Proceedings of the Royal Society of... 1977In a study using 14C-D-penicillamine in a normal subject only 50% of the D-penicillamine was absorbed from the gut. The major urinary metabolites are...
In a study using 14C-D-penicillamine in a normal subject only 50% of the D-penicillamine was absorbed from the gut. The major urinary metabolites are cysteine-penicillamine and penicillamine disulphide. S-methyl-D-penicillamine is the only biochemically transformed metabolite so far identified.
Topics: Amino Acids; Biotransformation; Cysteine; Feces; Half-Life; Humans; Penicillamine
PubMed: 122676
DOI: No ID Found -
Chinese Medical Journal Aug 2017
Topics: Humans; Isotretinoin; Male; Nicotinic Acids; Penicillamine; Skin Diseases; Triamcinolone Acetonide
PubMed: 28776563
DOI: 10.4103/0366-6999.211899 -
Proceedings of the Royal Society of... 1977
Review
Topics: Hepatolenticular Degeneration; Humans; Joint Diseases; Penicillamine
PubMed: 122670
DOI: No ID Found -
Dermatology Online Journal Apr 2011Long term D-penicillamine (DPA) therapy to treat Wilson disease can induce elastosis perforans serpiginosa (EPS), a very rare degenerative skin disease characterized by... (Review)
Review
Long term D-penicillamine (DPA) therapy to treat Wilson disease can induce elastosis perforans serpiginosa (EPS), a very rare degenerative skin disease characterized by a transepidermal elimination of elastic fiber aggregates. The iatrogenous disease depends on DPA capacity to chelate copper and cause its depletion. Lysyl-oxidase is a copper dependent enzyme crucial to the dermal elastic fiber cross-linking, which is strongly affected by DPA copper depletion. Direct binding of the drug to collagen precursors also affects elastic fiber assemblage and maturation. The abnormal elastin accumulates into the middle dermis and produces a characteristic bramble brush or "lumpy-bumpy" appearance. In this way it acts as a foreign body and is progressively extruded through the epidermis. Clinically, the disease presents with multiple firm keratotic papules and nodules arranged in annular plaques over the neck, axillae, antecubital fossae, and forearms. The rarity of the disease frequently causes misdiagnoses and the process continues unabated causing concerns about systemic elastopathy.
Topics: Adult; Chelating Agents; Cryotherapy; Hepatolenticular Degeneration; Humans; Male; Penicillamine; Skin Diseases; Treatment Outcome; Young Adult; Zinc
PubMed: 21549078
DOI: No ID Found