BIOMAT Database Logo BIOMAT Database Logo

Characterization of a chemically reactive propranolol metabolite that binds to microsomal proteins of rat liver. 1995

S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.

We have characterized a chemically reactive propranolol (PL) metabolite which binds to proteins in rat liver microsomes. During incubation with rat liver microsomes (1 mg of protein) fortified with an NADPH-generating system, 4-hydroxypropranolol (4-OH-PL) quickly disappeared from the reaction medium, but none of the possible metabolite peaks was detected under the high-performance liquid chromatographic conditions used. The consumption of 4-OH-PL depended on microsomes and NADPH. The reaction was not affected by inhibitors of cytochrome P450 or FAD monooxygenase, but was markedly diminished in the presence of cytosol and ascorbic acid. The effect of cytosol was inhibited by potassium cyanide but not by sodium benzoate or dimethyl sulfoxide, and was also not affected by heating at 60 degrees C for 30 min, suggesting that superoxide (SO) ion was involved in the reaction and that it was blocked by superoxide dismutase (SOD) present in the cytosol. Cu,Zn-SOD, purified from cytosol, effectively mimicked the suppressive effect of cytosol. Incubation of 4-OH-PL in an SO-generating system of xanthine and xanthine oxidase generated 1,4-naphthoquinone (1,4-NQ), which was identified by TLC, HPLC, and GC/MS. 1,4-NQ was also formed in microsomal incubates containing NADPH and small amounts of microsomes (below 0.1 mg of protein). These results indicate that 4-OH-PL is converted by SO, or some reactive oxygen species derived from it, to 1,4-NQ which binds to proteins and is one of the reactive metabolites of PL.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009285 Naphthoquinones Naphthalene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups. Naphthalenediones,Naphthazarins,Naphthoquinone
D011433 Propranolol A widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for MYOCARDIAL INFARCTION; ARRHYTHMIA; ANGINA PECTORIS; HYPERTENSION; HYPERTHYROIDISM; MIGRAINE; PHEOCHROMOCYTOMA; and ANXIETY but adverse effects instigate replacement by newer drugs. Dexpropranolol,AY-20694,Anaprilin,Anapriline,Avlocardyl,Betadren,Dociton,Inderal,Obsidan,Obzidan,Propanolol,Propranolol Hydrochloride,Rexigen,AY 20694,AY20694,Hydrochloride, Propranolol
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001711 Biotransformation The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.
D013057 Spectrum Analysis The measurement of the amplitude of the components of a complex waveform throughout the frequency range of the waveform. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Spectroscopy,Analysis, Spectrum,Spectrometry
D013481 Superoxides Highly reactive compounds produced when oxygen is reduced by a single electron. In biological systems, they may be generated during the normal catalytic function of a number of enzymes and during the oxidation of hemoglobin to METHEMOGLOBIN. In living organisms, SUPEROXIDE DISMUTASE protects the cell from the deleterious effects of superoxides. Superoxide Radical,Superoxide,Superoxide Anion

Related Publications

S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
The inhibition of rat hepatic microsomal propranolol metabolism by a covalently bound reactive metabolite.
February 1980, Research communications in chemical pathology and pharmacology,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Identification of human liver microsomal proteins adducted by a reactive metabolite using shotgun proteomics.
September 2014, Chemical research in toxicology,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Metabolic activation of (R)-(+)-pulegone to a reactive enonal that covalently binds to mouse liver proteins.
January 1989, Chemical research in toxicology,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Metabolic activation of trichloroethylene into a chemically reactive metabolite toxic to the liver.
March 1978, The Journal of pharmacology and experimental therapeutics,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
alpha-Methylepinephrine, a methyldopa metabolite that binds to alpha-receptors in rat brain.
January 1981, European journal of pharmacology,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Glutamate dehydrogenase covalently binds to a reactive metabolite of acetaminophen.
March 1996, Chemical research in toxicology,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Metabolic activation of para-chloroamphetamine to a chemically reactive metabolite.
January 1977, Communications in psychopharmacology,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Metabolic activation of furosemide to a chemically reactive, hepatotoxic metabolite.
October 1976, The Journal of pharmacology and experimental therapeutics,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Iminocyclophosphamide as a chemically reactive metabolite of cyclophosphamide.
January 1982, Drug metabolism and disposition: the biological fate of chemicals,
S Narimatsu, and T Watanabe, and Y Masubuchi, and T Horie, and Y Kumagai, and A K Cho, and S Imaoka, and Y Funae, and T Ishikawa, and T Suzuki
Covalent binding of [14C]methoxychlor metabolite(s) to rat liver microsomal components.
May 1983, Toxicology and applied pharmacology,
Copied contents to your clipboard!