Reduction of the C2 and C4 vinyl groups of Sn-protoporphyrin to form Sn-mesoporphyrin markedly enhances the ability of the metalloporphyrin to inhibit in vivo heme catabolism |
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| Authors: | G S Drummond R A Galbraith M K Sardana A Kappas |
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| Institution: | 1. Department of Computer Science and Engineering, Yuan Ze University, 32003, Taiwan;2. School of Humanities, Nanyang Technological University, 50 Nanyang Ave., 639798, Singapore;1. Department of Parasitology and Tropical Medicine, and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Republic of Korea;2. Division of Malaria and Parasitic Diseases, National Institute of Health, Korea Centers for Disease Control and Prevention, Osong 363-951, Republic of Korea;3. Department of Microbiology, Institute of Health Sciences and PMBBRC, Gyeongsang National University School of Medicine, Jinju 660-751, Republic of Korea;4. Department of Tropical Medicine, and Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon 400-712, Republic of Korea;1. Professor, Department of Microbiology, Armed Forces Medical College, Pune 411040, India;2. Senior Advisor (Medicine & Respiratory Med), Military Hospital (Cardio Thoracic Centre), Pune 411040, India;3. Classified Specialist (Pathology & Microbiology), Army Hospital (R&R), New Delhi, India;4. Professor and Head (Microbiology), SGPGIMS, Lucknow, India;5. Professor and Head (Botany), University of Lucknow, Lucknow, India;1. School of Economics and Finance, Faculty of Business and Economics, The University of Hong Kong, Hong Kong;2. Research Department, The Federal Reserve Bank of Kansas City, United States;3. Department of Economics, University of Virginia, Charlottesville, VA 22904, United States |
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| Abstract: | Sn (tin)-mesoporphyrin (Sn-protoporphyrin in which the vinyl groups at C2 and C4 have been reduced to ethyl groups) when incubated with rat splenic microsomal heme oxygenase proved to be a potent competitive inhibitor of enzyme activity in vitro, with a Ki of 0.014 microM. Sn-mesoporphyrin (1 mumol/kg body wt) also inhibited hepatic, renal, and splenic heme oxygenase activity in vivo in adult animals for extended periods of time. Sn-mesoporphyrin (1 mumol/kg body wt) prevented the transient increase in serum bilirubin 24 h after birth in the rat neonate and substantially reduced the levels of serum bilirubin in ALA (delta-aminolevulinic acid) induced hyperbilirubinemia in the 7-day-old suckling neonate. Tissue heme oxygenase activity was decreased in both animal models of hyperbilirubinemia. Sn-mesoporphyrin administration led to a prolonged increase in the heme saturation of hepatic tryptophan pyrrolase indicating an increase in the "heme pool" related to tryptophan pyrrolase and the compound also suppressed chemically induced hepatic porphyria. The administration of Sn-mesoporphyrin to bile duct-cannulated rats was followed by a prompt and sustained decrease in bilirubin output in bile. In addition the excretion of heme in bile was enhanced in these animals. These studies indicate that Sn-mesoporphyrin, like Sn-protoporphyrin, decreases serum bilirubin by inhibiting the production of bilirubin in vivo and its mode of action is through a sustained competitive inhibition of heme oxygenase. However, when a direct comparison of Sn-protoporphyrin and Sn-mesoporphyrin was made, these studies clearly established that the reduction of the C2 and C4 vinyl groups of the porphyrin macrocycle to ethyl groups increases the effectiveness of the Sn-mesoporphyrin derivative 10-fold or more as compared with Sn-protoporphyrin in inhibiting heme catabolism in the animal model systems examined. Thus alterations in the side chain substituents as well as of the central metal atom can influence in a significant manner the potency of the resultant synthetic heme analog as an agent capable of inhibiting heme degradation in vivo. |
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