Interaction of chemicals with cytochrome P-450: implications for the porphyrinogenicity of drugs.
Our studies lead us to suggest that in order for an organic chemical to cause porphyrin accumulation in chick embryo hepatocyte culture, it must be: 1. lipophilic; 2. resistant to biotransformation by phase I or phase II reactions to compounds which are devoid of biological activity; and 3. capable of interacting with cytochrome P-450 with concomitant destruction of the heme moiety or the generation of reactive oxygen species. The interaction of porphyrin-inducing chemicals with cytochrome P-450 results in lowering of a regulatory "free heme" pool. The "free heme" pool may be lowered by inhibiting one or more of the enzymes of heme biosynthesis or by destruction of the heme moiety of cytochrome P-450. Specific chemical features enable organic chemicals to inhibit ferrochelatase activity or to destroy the heme moiety of cytochrome P-450. Chemicals with a wide variety of structures are able to inhibit uroporphyrinogen decarboxylase activity.
Marks
G S
GS
Department of Pharmacology and Toxicology, Queen's University, Ontario, Canada.
McCluskey
S A
SA
Mackie
J E
JE
Riddick
D S
DS
James
C A
CA
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D011164:Porphyrias / Q000378:metabolism; D011166:Porphyrins / Q000096:biosynthesis* / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism
D006571:Heterocyclic Compounds; D011166:Porphyrins; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D000624:5-Aminolevulinate Synthetase; D014575:Uroporphyrinogen Decarboxylase