In the past, we have identified the ability of metal ions and environmental toxins to induce heme oxygenase activity in various organs and thus defined a unified mechanism by which environmental agents alter cellular heme and hemoprotein metabolism activities. Such alterations can be reflected in perturbations in biological functions and biotransformation reactions which depend on hemoproteins. This includes drug, xenobiotic, and steroid metabolism activities. Recently we have identified in rat liver and testis the presence of two forms of heme oxygenase. We have referred to these as HO-1 and HO-2. HO-1 was purified to homogeneity from the liver of animals treated with environmental chemicals and HO-2 was purified from the testis of control animals. The preparations differed in molecular weight, antigenicity, kinetic properties and thermolability. However, a most intriguing difference between the two isoforms was the difference in their regulatory mechanism. The HO-1 activity could be increased by nearly 100- fold by acutely exposing rats to toxic chemicals and metal ions (e.g. bromobenzene, cobalt and cadmium) without effecting the HO-2 activity. Curiously, HO-2, in the control state, constitutes the major form of the enzyme in both the liver and the testis. The overall objective of the proposed research is to further characterize the isoforms of heme oxygenase at molecular, biochemical, and toxicological levels.
The specific aims of the proposed research are: a) to isolate the isoforms of heme oxygenase from rat liver and testis, and compare the isoforms for immunochemical and biochemical properties, as well as response to environmental chemical and physiological manipulations; b) to examine the occurrence of multiple forms of heme oxygenase in other mammalian species; c) to isolate cDNA clones for heme oxygenase isoforms, and to determine the primary and secondary structure of the proteins; d) to investigate regulation of isoform specific induction of heme oxygenase by metal ions and chemical and e) to elucidate the genetic basis for HO multiplicity. We anticipate that the studies proposed here will begin to unravel, at a molecular level, the mechanism(s) by which a host of unrelated chemicals regulate heme oxygenase activity, and will aid in delineating the biological significance of the multiplicity of the enzyme.
|Maines, Mahin D (2002) Heme oxygenase 1 transgenic mice as a model to study neuroprotection. Methods Enzymol 353:374-88|
|Ahmad, Zulfiqar; Salim, Mohammad; Maines, Mahin D (2002) Human biliverdin reductase is a leucine zipper-like DNA-binding protein and functions in transcriptional activation of heme oxygenase-1 by oxidative stress. J Biol Chem 277:9226-32|
|Salim, M; Brown-Kipphut, B A; Maines, M D (2001) Human biliverdin reductase is autophosphorylated, and phosphorylation is required for bilirubin formation. J Biol Chem 276:10929-34|
|Panahian, N; Maines, M D (2001) Site of injury-directed induction of heme oxygenase-1 and -2 in experimental spinal cord injury: differential functions in neuronal defense mechanisms? J Neurochem 76:539-54|
|Maines, M D; Panahian, N (2001) The heme oxygenase system and cellular defense mechanisms. Do HO-1 and HO-2 have different functions? Adv Exp Med Biol 502:249-72|
|Maines, M D; Ewing, J F; Huang, T J et al. (2001) Nuclear localization of biliverdin reductase in the rat kidney: response to nephrotoxins that induce heme oxygenase-1. J Pharmacol Exp Ther 296:1091-7|
|Huang, T J; McCoubrey Jr, W K; Maines, M D (2001) Heme oxygenase-2 interaction with metalloporphyrins: function of heme regulatory motifs. Antioxid Redox Signal 3:685-96|
|Chen, K; Gunter, K; Maines, M D (2000) Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. J Neurochem 75:304-13|
|Liu, N; Wang, X; McCoubrey, W K et al. (2000) Developmentally regulated expression of two transcripts for heme oxygenase-2 with a first exon unique to rat testis: control by corticosterone of the oxygenase protein expression. Gene 241:175-83|
|Ding, Y; McCoubrey Jr, W K; Maines, M D (1999) Interaction of heme oxygenase-2 with nitric oxide donors. Is the oxygenase an intracellular 'sink' for NO? Eur J Biochem 264:854-61|
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