Disruption of hepatic heme biosynthesis after interaction of xenobiotics with cytochrome P-450.
Heme biosynthesis in hepatocytes is controlled by a free heme pool, which regulates delta-aminolevulinic acid synthase. Porphyrinogenic chemicals deplete the regulatory free heme pool by interacting with cytochrome P-450 thereby inhibiting heme biosynthesis and/or causing heme breakdown. Recent developments allow us to predict which groups of chemicals are likely to be porphyrinogenic. One group is exemplified by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine. Heterocyclic compounds of this type cause mechanism-based inactivation of cytochrome P-450, leading to the formation of N-alkylporphyrins, with ferrochelatase-inhibitory activity resulting in lowering the free heme pool. Allylisopropylacetamide exemplifies a second group. Such compounds containing a terminal olefinic or acetylenic group, cause mechanism-based inactivation of cytochrome P-450. In the process, the heme moiety of cytochrome P-450 is destroyed and the free heme pool is lowered. A third group is exemplified by planar polyhalogenated or polycyclic aromatic hydrocarbons. These compounds induce specific cytochrome P-450 isozymes but are poor substrates. Active oxygen is formed, which interacts with a hepatic substrate to form a uroporphyrinogen decarboxylase inhibitor. Inhibition of this enzyme leads to depletion of the free heme pool.
D000478:Alkylation; D000818:Animals; D001696:Biomechanical Phenomena; D002478:Cells, Cultured; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004347:Drug Interactions; D005294:Ferrochelatase / Q000037:antagonists & inhibitors; D006418:Heme / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D010600:Pharmacology; D011166:Porphyrins / Q000096:biosynthesis / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D011166:Porphyrins; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D014575:Uroporphyrinogen Decarboxylase; D005294:Ferrochelatase