Porphyrinogenic activity and ferrochelatase-inhibitory activity of sydnones in chick embryo liver cells

• Published in: FEBS letters Vol. 197; no. 1; pp. 17 - 20
• Main Authors: Sutherland, E.P., Marks, G.S., Grab, L.A., de Montellano, P.R.Ortiz
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 03.03.1986; Elsevier
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; Chick Embryo; Cytochrome P-450 Enzyme System - physiology; Dicarbethoxydihydrocollidine - pharmacology; Ferrochelatase - antagonists & inhibitors; General pharmacology; Liver - drug effects; Liver - metabolism; Lyases - antagonists & inhibitors; Medical sciences; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Porphyria Ferrochelatase N-Alkylprotophyrm Sydnone Cytochrome P-450 (Chick embryo liver); Porphyrins - biosynthesis; Protoporphyrins - biosynthesis; Sydnones - pharmacology; Porphyria Ferrochelatase N-Alkylprotophyrm Sydnone Cytochrome P-450 (Chick embryo liver); Porphyrin; Cytochrome P450; Photochemical reaction
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/0014-5793(86)80289-7

3-[2-(2,4,6-Trimethylphenyl)thioethyl]-4-methylsydnone was shown to be a potent porphyrinogenic agent in chick embryo liver cells. The accumulation of protoporphyrin IX was consistent with the finding that ferrochelatase activity was inhibited. 3-Benzyl-4-phenylsydnone did not inhibit ferrochelatase activity and protoporphyrin IX was found to constitute only a minor fraction of the porphyrins. These results support the idea that the porphyrinogenicity of 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone is due to its catalytic activation by cytochrome P-450 leading to heme alkylation and formation of N-vinylprotoporphyrin IX which inhibits ferrochelatase.