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Prolonged induction of hepatic haem oxygenase and decreases in cytochrome P-450 content by organotin compounds.

ABSTRACT: The administration of organotin compounds to rats in single doses causes a significant and prolonged induction of haem oxygenase and a sustained decrease in haemoprotein content in the liver. The extent of induction of hepatic haem oxygenase varied between 3 and 5-fold at 72h after a single injection of water-insoluble organotins of differing structure. The alterations in haem metabolism produced by tricyclohexyltin hydroxide were studied in detail. The effects were dose-dependent, with doses as low as 3.75 mg/kg body wt. resulting in significant induction of haem oxygenase and a decrease in cytochrome P-450 and cytochrome b5 contents at 72h in the liver. The effects with time of a single dose of tricyclohexyltin on various parameters of liver haem metabolism were also examined. The organotin produced a substantial and very prolonged induction of haem oxygenase accompanied by a steady decline in cytochrome P-450 content for periods up to 8 days. The long duration of action of these organotins with respect to induction of haem oxygenase and depletion of cellular haemoprotein content provides a highly sensitive metabolic system with which to define further the toxic potential of organometals as well as to study the adaptive responses in liver to long-term perturbations of haem metabolism by foreign chemicals.

SUBMITTER: Rosenberg DW

PROVIDER: S-EPMC1162114 | biostudies-other | 1980 Aug

REPOSITORIES: biostudies-other

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Project description:HO-1 (haem oxygenase 1) is an essential antioxidant enzyme in the cell that exerts its effects through removal of pro-oxidant haem groups and the formation of antioxidant molecules and carbon monoxide. The electrophilic cyclopentenone 15d-PGJ2 (15-deoxy-Delta(12,14)-prostaglandin J2) induces the expression of HO-1 protein through the covalent modification of protein thiols. It has been shown that specific thiol residues of the redox-sensor Keap1 (Kelch-like ECH-associated protein 1) are modified by 15d-PGJ2, leading to activation of the transcription factor Nrf-2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) and up-regulation of genes under control of the electrophile-response element, including HO-1. However, 15d-PGJ2 has also been shown to modify other proteins which comprise the electrophile-responsive proteome. Since 15d-PGJ2 has been shown to localize to the mitochondria in endothelial cells, we hypothesized that mitochondrial protein modification may also be important in Keap1/Nrf-2 signal transduction, leading to HO-1 up-regulation. In order to determine the role of mitochondrial protein thiol modification in HO-1 induction, we used the mitochondrial-targeted thiol-reactive compound IBTP [(4-iodobutyl)triphenylphosphonium]. IBTP had no effect on basal HO-1 levels, but effectively blocked HO-1 induction by a variety of reagents including haemin, iodoacetamide and 15d-PGJ2. Mechanistically, IBTP did not prevent the covalent modification of Keap1 by 15d-PGJ2. However, IBTP prevented the 15d-PGJ2-dependent increases in HO-1 mRNA and protein. Furthermore, IBTP prevented the nuclear accumulation of Nrf-2, suggesting cross-talk between mitochondria and antioxidant-response signal transduction. This effect was independent of reactive oxygen species formation or mitochondrial membrane potential. In addition, IBTP significantly enhanced the toxicity of high concentrations of 15d-PGJ2, suggesting that loss of mitochondrial control of HO-1 leads to increased susceptibility to electrophilic stress in endothelial cells. The implications for these studies in understanding the balance between cytoprotection and cytotoxicity in the context of diseases such as atherosclerosis is discussed.

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Prolonged induction of hepatic haem oxygenase and decreases in cytochrome P-450 content by organotin compounds.

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