N-Methylprotoporphyrin is a more potent inhibitor of recombinant human than of recombinant chicken ferrochelatase.
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 EC(50) values of N-methylPP previously observed in crude chick embryo liver FC was 2.9 x 10(-3) nmol/mg protein, and with purified recombinant chicken FC was 2.07 x 10(-3) nmol/mg protein. The difference in EC(50) values 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 of N-methylPP. The second objective of this study was to compare the potency of N-methylPP between purified human and chicken FC. The EC(50) value of N-methylPP observed in the purified human FC preparation was 1.7 x 10(-6) nmol/mg protein (chicken FC 2.07 x 10(-3) nmol/mg protein). Thus, the potency of N-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.
Gamble
J T
JT
Department of Pharmacology and Toxicology,Faculty of Health Sciences Queen's University, Kingston, Ontario, Canada.
Dailey
H A
HA
Marks
G S
GS
D000818:Animals; D002645:Chickens; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D006801:Humans; D011524:Protoporphyrins / Q000302:isolation & purification / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D011524:Protoporphyrins; D011994:Recombinant Proteins; C028842:N-methylprotoporphyrin IX; D005294:Ferrochelatase