Abstract
The potency of N-methylprotoporphyrin IX (N-methylPP) as a ferrochelatase (FC) inhibitor has been previously studied using crude chick embryo liver FC preparations. However, interactions between N-methylprotoporphyrin IX (N-methylPP) and impurities in the enzyme preparation may have compromised the results. The first objective of this study was to compare the potency of N-methylPP as an inhibitor of purified chicken FC and crude chick embryo liver FC. The EC50 values of N-methylPP previously observed in crude chick embryo liver FC was 2.9 × 10−3nmol/mg protein, and with purified recombinant chicken FC was 2.07 × 10−3 nmol/mg protein. The difference in EC50values was not statistically significant, and we conclude that interactions between N-methylPP and impurities in crude enzyme preparations did not affect the estimation of potency ofN-methylPP. The second objective of this study was to compare the potency of N-methylPP between purified human and chicken FC. The EC50 value ofN-methylPP observed in the purified human FC preparation was 1.7 × 10−6 nmol/mg protein (chicken FC 2.07 × 10−3 nmol/mg protein). Thus, the potency ofN-methylPP was much higher with purified human FC than with purified chicken FC. Because the porphyrinogenicity of several xenobiotics involves N-alkylprotoporphyrin IX formation, results on drug-induced porphyria obtained with avian species may underestimate the potential porphyrinogenicity in humans.
Footnotes
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Send reprint requests to: Gerald S. Marks, Ph.D., Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Ontario, Canada K7L 3N6. E-mail:gsm{at}post.queensu.ca
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This work was supported by the Medical Research Council of Canada.
- Abbreviations used are::
- N-alkylPP
- N-alkylprotoporphyrin IX
- N-methylPP
- N-methylprotoporphyrin IX
- FC
- ferrochelatase
- Received August 27, 1999.
- Accepted November 30, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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