Control of heme and cytochrome P-450 metabolism by inorganic metals, organometals and synthetic metalloporphyrins
The heme-cytochrome P-450 complexes represent sensitive metabolic systems for examining the biological impact of metals on important cellular functions. Many metals, both in the inorganic form and bound to organic moieties, potently induce heme oxygenase, the rate limiting enzyme of heme degradation. The resulting increase in the rate of heme breakdown is reflected in a marked depression of cellular cytochrome P-450 content and impairment of the oxidative metabolism of natural and foreign chemicals dependent on this hemoprotein. Organometal complexes do not mimic in all their aspects the actions of the inorganic elements which they contain. For example, organotins, in contrast to inorganic tin, produce a prolonged induction response of heme oxygenase in the liver but not in the kidney. Co-protoporphyrin is a much more potent inducer of heme oxygenase in liver than is inorganic cobalt; and Sn-protoporphyrin inhibits heme oxygenase activity nearly completely, whereas inorganic tin is a powerful inducer of the renal enzyme. Contrasting effects on heme metabolism exist as well within the metalloporphyrin species as demonstrated by the effects in vivo of Co-protoporphyrin and Sn-protoporphyrin on heme oxygenase activity; the former induces the enzyme whereas the latter potently inhibits it. In vitro, however, both compounds competitively inhibit heme oxidation activity. These differences, among others which characterize metal actions in vivo and in vitro attest to the importance of pharmacokinetic, adaptive and other host factors in defining the responses of the heme-cytochrome P-450 systems to the impact of metals in the whole animal. 21 references, 8 figures, 1 table.
- Research Organization:
- Rockefeller Univ. Hospital, New York, NY
- OSTI ID:
- 5606840
- Journal Information:
- Environ. Health Perspect.; (United States), Vol. 57
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
COBALT
BIOLOGICAL EFFECTS
CYTOCHROMES
METABOLISM
HEME
ORGANOMETALLIC COMPOUNDS
OXYGENASES
ENZYME ACTIVITY
PROTOPORPHYRINS
TIN
BIOCHEMICAL REACTION KINETICS
ENZYME INHIBITORS
KIDNEYS
LIVER
BODY
CARBOXYLIC ACIDS
DIGESTIVE SYSTEM
ELEMENTS
ENZYMES
GLANDS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
KINETICS
METALS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDOREDUCTASES
PIGMENTS
PORPHYRINS
REACTION KINETICS
TRANSITION ELEMENTS
560305* - Chemicals Metabolism & Toxicology- Vertebrates- (-1987)