Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria
Acute intermittent porphyria (AIP) is characterized by acute neurovisceral attacks that are precipitated by the induction of hepatic 5-aminolevulinic acid synthase 1 (ALAS1). In erythropoietic protoporphyria (EPP), sun exposure leads to skin photosensitivity due to the overproduction of photoreactiv...
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MDPI AG
2023-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/1/27 |
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| author | Makiko Yasuda Sangmi Lee Lin Gan Hector A. Bergonia Robert J. Desnick John D. Phillips |
| author_facet | Makiko Yasuda Sangmi Lee Lin Gan Hector A. Bergonia Robert J. Desnick John D. Phillips |
| author_sort | Makiko Yasuda |
| collection | DOAJ |
| description | Acute intermittent porphyria (AIP) is characterized by acute neurovisceral attacks that are precipitated by the induction of hepatic 5-aminolevulinic acid synthase 1 (ALAS1). In erythropoietic protoporphyria (EPP), sun exposure leads to skin photosensitivity due to the overproduction of photoreactive porphyrins in bone marrow erythroid cells, where heme synthesis is primarily driven by the ALAS2 isozyme. Cimetidine has been suggested to be effective for the treatment of both AIP and EPP based on limited case reports. It has been proposed that cimetidine acts by inhibiting ALAS activity in liver and bone marrow for AIP and EPP, respectively, while it may also inhibit the hepatic activity of the heme catabolism enzyme, heme oxygenase (HO). Here, we show that cimetidine did not significantly modulate the activity or expression of endogenous ALAS or HO in wildtype mouse livers or bone marrow. Further, cimetidine did not effectively decrease hepatic ALAS activity or expression or plasma concentrations of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which were all markedly elevated during an induced acute attack in an AIP mouse model. These results show that cimetidine is not an efficacious treatment for acute attacks and suggest that its potential clinical benefit for EPP is not via ALAS inhibition. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-08T11:04:40Z |
| publishDate | 2023-12-01 |
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| record_format | Article |
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| spelling | doaj.art-b2a9a0093e7c481e8dbbc7536f5301e42024-01-26T15:18:03ZengMDPI AGBiomolecules2218-273X2023-12-011412710.3390/biom14010027Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic ProtoporphyriaMakiko Yasuda0Sangmi Lee1Lin Gan2Hector A. Bergonia3Robert J. Desnick4John D. Phillips5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave Box 1498, New York, NY 10029, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave Box 1498, New York, NY 10029, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave Box 1498, New York, NY 10029, USADepartment of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, UT 84132, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave Box 1498, New York, NY 10029, USADepartment of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, UT 84132, USAAcute intermittent porphyria (AIP) is characterized by acute neurovisceral attacks that are precipitated by the induction of hepatic 5-aminolevulinic acid synthase 1 (ALAS1). In erythropoietic protoporphyria (EPP), sun exposure leads to skin photosensitivity due to the overproduction of photoreactive porphyrins in bone marrow erythroid cells, where heme synthesis is primarily driven by the ALAS2 isozyme. Cimetidine has been suggested to be effective for the treatment of both AIP and EPP based on limited case reports. It has been proposed that cimetidine acts by inhibiting ALAS activity in liver and bone marrow for AIP and EPP, respectively, while it may also inhibit the hepatic activity of the heme catabolism enzyme, heme oxygenase (HO). Here, we show that cimetidine did not significantly modulate the activity or expression of endogenous ALAS or HO in wildtype mouse livers or bone marrow. Further, cimetidine did not effectively decrease hepatic ALAS activity or expression or plasma concentrations of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which were all markedly elevated during an induced acute attack in an AIP mouse model. These results show that cimetidine is not an efficacious treatment for acute attacks and suggest that its potential clinical benefit for EPP is not via ALAS inhibition.https://www.mdpi.com/2218-273X/14/1/27porphyriasacute intermittent porphyriaerythropoietic protoporphyriadisorders of heme biosynthesistherapies for porphyriascimetidine |
| spellingShingle | Makiko Yasuda Sangmi Lee Lin Gan Hector A. Bergonia Robert J. Desnick John D. Phillips Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria Biomolecules porphyrias acute intermittent porphyria erythropoietic protoporphyria disorders of heme biosynthesis therapies for porphyrias cimetidine |
| title | Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria |
| title_full | Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria |
| title_fullStr | Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria |
| title_full_unstemmed | Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria |
| title_short | Cimetidine Does Not Inhibit 5-Aminolevulinic Acid Synthase or Heme Oxygenase Activity: Implications for Treatment of Acute Intermittent Porphyria and Erythropoietic Protoporphyria |
| title_sort | cimetidine does not inhibit 5 aminolevulinic acid synthase or heme oxygenase activity implications for treatment of acute intermittent porphyria and erythropoietic protoporphyria |
| topic | porphyrias acute intermittent porphyria erythropoietic protoporphyria disorders of heme biosynthesis therapies for porphyrias cimetidine |
| url | https://www.mdpi.com/2218-273X/14/1/27 |
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