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Vol. 286, Issue 3, 1253-1259, September 1998
Department of Drug Disposition, Lilly Research Laboratories, Eli
Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana (S.E.,
M.V., B.J.R., J.S.G., S.A.W.) and
National Cancer Institute, Bethesda,
Maryland (T.J.Y., H.V.G.)
Previous studies in this laboratory have determined the lack of
specificity of several antibody and substrate probes of CYP2B6. The
goals of the current study were to examine the expression of CYP2B6 in
a bank of human liver microsome (HLM) samples using a new specific
monoclonal antibody (MAb 49-10-20) and to further characterize the
substrate specificity of CYP2B6. A 100-fold variability in expression
of immunodetectable CYP2B6 was demonstrated in a bank of 19 HLM samples
(0.7 pmol/mg protein to 71.1 pmol/mg protein) using MAb 49-10-20. CYP2B6 levels were found to significantly (P < .0001) correlate
with S-mephenytoin N-demethylation to nirvanol (r2 = 0.89), 7-hydroxy-4-trifluoromethylcoumarin formation
(r2 = 0.81) and several markers of CYP3A levels and
activity. The relationships between nirvanol formation and CYP3A levels
or activity were found to depend on two HLM samples.
Km (apparent) values were generated for
benzyloxyresorufin O-deethylation (1.3 µM), benzphetamine
N-demethylation (93.4 µM), 3-cyano 7-ethoxycoumarin O-deethylation (71.3 µM), midazolam 1'-hydroxylation (46.1 µM) and 4-chloromethyl-7-ethoxycoumarin O-deethylation
(33.7 µM) using expressed CYP2B6. Testosterone 16
-hydroxylation by
expressed CYP2B6 resulted in atypical kinetics characteristic of
substrate activation. The data best fit the Hill equation with a
Km (apparent) of 50.5 µM and an n
of 1.3 (n = number of sites bound by activator). In
conclusion, the highly specific MAb 49-10-20 was used to provide further confirmation that S-mephenytoin
N-demethylation to nirvanol is a CYP2B6 selective probe.
Finally, some, but not all substrates of CYP2B6 demonstrate
autoactivation.
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