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The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Farmington, Connecticut, USA
1Correspondence: The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, Farmington, CT 06030, USA.
We thank Dr. Schmidt for the expressed interest in our recent work. We agree that up-regulation of heme oxygenase-1 activity may provide benefit in a multiplicity of pathophysiologic states. Indeed, there is already a large and rapidly growing literature on the potential beneficial effects of increasing activity of heme oxygenase. Some of these recent papers and reviews are referred to in our paper, and others are in the letter from Dr. Schmidt.
We also agree that there may be unwanted side effects of cobalt protoporphyrin and that such side effects may not exist (or be different in profile) compared with volatile anesthetics such as isoflurane and sevoflurane. In regard to Dr. Schmidt's unpublished results, we and others would be interested to know more details about the experiments in which animals received single injections of 5 mg/kg cobalt protoporphyrin, and in what cell type or cell lines Dr. Schmidt observed evidence of LDH release following exposure to 2.5 micromolar cobalt protoporphyrin and for what duration of exposure.
As reported in our manuscript, exposure to as low as 0.5 µM of cobalt protoporphyrin significantly increased HO-1 mRNA levels, and 25 µM cobalt protoporphyrin caused cell toxicity in Huh-7 cells (1)
. However, as reported in our previous study, 5 µM cobalt protoporphyrin significantly increased the HO-1 promoter/reporter gene activity, whereas 30 µM cobalt protoporphyrin was required to cause detectable cell toxicity in chick embryo liver cells (CELC) in primary culture and in a chick liver hepatoma cell line (LMH) (2)
. Our unpublished data indicate that 100 µM cobalt protoporphyrin significantly increases HO-1 mRNA levels without producing detectable cell toxicity in human Caco-2 cells. We also found that if cobalt protoporphyrin is pre-mixed with 1% BSA, the cell toxicity caused by cobalt protoporphyrin is reduced. For example, cobalt protoporphyrin concentrations up to 40 µM with 1% BSA do not produce cell toxicity in CELC or LMH cells. Therefore, the concentrations of cobalt protoporphyrin needed to up-regulate HO-1 gene expression and/or to produce evidence of cytotoxicity vary widely across different cell lines and reagent preparations.
We look forward to hear more about the clinical trial recently initiated by Dr. Schmidt and colleagues.
FOOTNOTES
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals@faseb.org.
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