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Regulation of cytochrome P‐450‐dependent microsomal drug‐metabolizing enzymes by nickel, cobalt, and iron
Author(s) -
Maines Mahin D.,
Kappas Attallah
Publication year - 1977
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt1977225part2780
Subject(s) - heme , glutathione , chemistry , enzyme , biochemistry , metabolite , drug metabolism , microsome , biotransformation , cytochrome p450 , cobalt , cytochrome , metabolism , drug , toxicity , pharmacology , biology , inorganic chemistry , organic chemistry
The effects of metals as modifiers of the activity of microsomal drug‐metabolizing enzymes were studied with the use of nickel, cobalt, and iron. These metals were found to impair cellular heme‐dependent metabolism by affecting both the heme biosynthetic and heme degradative pathways, inhibiting the former and inducing the latter. As powerful cellular toxins, metals depress respiratory activity and indirectly reduce drug‐detoxifying ability of cells. Metals also perturb cellular glutathione content and thus may alter the activity of glutathione‐dependent enzymes. The toxicity of metals is cumulative depending on concentration and degree of cellular exposure to one or to several closely related metals. On the other hand, these metal effects on cellular heme metabolism could also have selective therapeutic application in circumstances in which it may be desirable to suppress heme synthesis in order to decrease drug biotransformation, i.e., when a certain drug metabolite is more toxic than the parent compound.