Abstract
THE JOURNAL OF PHARMACOLOGY
AND EXPERIMENTAL THERAPEUTICS Vol. 305, No. 1
Copyright © 2003 by The American Society for Pharmacology and Experimental
Therapeutics 47050/1051632
JPET 305:315–322, 2003 Printed in U.S.A.
Contribution
of Individual Cytochrome P450 Isozymes to the
O-Demethylation of the Psychotropic B-Carboline Alkaloids
Harmaline and Harmine
AI-MING YU, JEFFREY R.
IDLE,1 KRISTOPHER W. KRAUSZ, ADRIAN KU¨ PFER, and FRANK J. GONZALEZ
Laboratory of Metabolism, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland (A.-M.Y., K.W.K, F.J.G.), and Department of Clinical
Pharmacology, University of Bern, Bern, Switzerland (J.R.I., A.K.)
Received November 19, 2002; accepted December 30, 2002
ABSTRACT
The psychotropic B-carboline alkaloids, showing high affinity
for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline
receptors and the stimulation of locus coeruleus neurons,
are formed endogenously from tryptophan-derived indolealkylamines
through the Pictet-Spengler condensation with
aldehydes in both plants and mammals. Cytochromes P450
1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation
of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9
(16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of
harmine (relative activities). The dehydrogenation/aromatization
of harmaline to harmine was not carried out by aromatase
(CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant
cytochromes P450, or human liver microsomes (HLMs).
Kinetic parameters were calculated for the O-demethylations
mediated by each isozyme and by pooled HLMs. Kcat (min1)
and Km (M) values for harmaline were: CYP1A1, 10.8 and
11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19,
10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine
were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9,
11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and
7.4. Inhibition studies using monoclonal antibodies confirmed
that CYP1A2 and CYP2D6 were the major isozymes contributing
to both harmaline (20% and 50%, respectively) and harmine
(20% and 30%) O-demethylations in pooled HLMs. The turnover
numbers for CYP2D6 are among the highest ever reported
for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were
found to have increased harmaline and harmine O-demethylase
activities as compared with wild-type mice. These findings
suggest a role for polymorphic CYP2D6 in the pharmacology
and toxicology of harmine and harmaline.
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