RT Journal Article
SR Electronic
T1 CYP1A2 and CYP2D6 4-Hydroxylate Propranolol and Both Reactions Exhibit Racial Differences
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1099
OP 1105
VO 294
IS 3
A1 Johnson, Julie A.
A1 Herring, Vanessa L.
A1 Wolfe, Michael S.
A1 Relling, Mary V.
YR 2000
UL http://jpet.aspetjournals.org/content/294/3/1099.abstract
AB We have previously shown racial differences in propranolol kinetics, with the largest differences appearing to be in its 4-hydroxylation. The purpose of this study was to identify and confirm the cytochrome P450 enzymes (CYP) with propranolol 4-hydroxylase activity, describe their enzyme kinetics, and determine whether there were racial differences in their catalytic activity. Eleven human recombinant, expressed CYPs were screened, but only CYP1A2 and CYP2D6 possessed propranolol 4-hydroxylase activity. Subsequent studies were conducted in human liver microsomes, including correlation, inhibition, enzyme kinetics, and racial comparison studies. Significant correlations were noted between propranolol 4-hydroxylation and ethoxyresorufin-O-deethylation (marker of CYP1A2 activity), with marked improvement in the correlations when CYP2D6-mediated propranolol 4-hydroxylation was inhibited with quinidine. Inhibition studies showed that quinidine inhibited approximately 55% of propranolol 4-hydroxylation and furaphylline (CYP1A2-selective inhibitor) inhibited about 45% of propranolol 4-hydroxylation. Median (range) parameter estimates of (S)-4-hydroxypropranolol [(S)-HOP] formation were a Vmax value of 307 (165–2397) and 721 (84–1975) pmol/mg of protein/60 min for CYP1A2 and CYP2D6, respectively, and a Km value of 21.2 (8.9–77.5) and 8.5 (5.9–31.9) μM for CYP1A2 and CYP2D6, respectively. CYP1A2- and CYP2D6-mediated propranolol 4-hydroxylation was about 70 and 100% higher (P < .05 for both), respectively, in African-Americans compared with Caucasians. In summary, we found that both CYP1A2 and CYP2D6 catalyze formation of 4-hydroxypropranolol and that both enzymes exhibited racial differences in this reaction. The observed racial differences in drug metabolism may have relevance to drug efficacy, toxicity, or carcinogen activation for CYP1A2 or CYP2D6 substrates. The American Society for Pharmacology and Experimental Therapeutics