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Vol. 28, Issue 10, 1202-1209, October 2000
TNO BIBRA International Ltd., Surrey, United Kingdom
(A.B.R., P.T.B., R.J.P., B.G.L.); Section on Clinical Pharmacology,
Division of Medicine, Imperial College School of Medicine, Hammersmith
Hospital, London, United Kingdom (P.S.W., R.J.E., A.R.B.); ENS
BANA, Université de Bourgogne, Dijon, France
(I.G.); Institute of Liver Studies, Guy's, King's and St. Thomas'
School of Medicine, London, United Kingdom (J.M.T.); and Department of
Pharmacology and Toxicology, University of Oulu, Oulu, Finland (O.P.)
The maintenance of the major hepatic cytochrome P450 (CYP) enzymes
has been studied in precision-cut human liver slices cultured for up to
72 h in supplemented RPMI 1640 medium. The relative apoprotein
levels of 11 CYP enzymes were determined using a panel of antipeptide
antibodies. In addition, 7-ethoxyresorufin O-deethylase, tolbutamide methylhydroxylase, debrisoquine 4-hydroxylase, and testosterone 6
-hydroxylase activities were determined as enzymatic markers for CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively. There was
a large variation in the rate of decline of different CYP levels with
time in culture. Based on the rate of decrease, CYP enzymes could be
separated into two groups, with CYP2C9, CYP2D6, CYP3A4, and CYP4A11
being relatively stable (half-lives between 70 and 104 h),
compared with CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, and
CYP3A5, which were relatively unstable (half-lives between 23 and
36 h). Enzyme activities decreased at rates similar to those of
their corresponding apoproteins. There was also a large difference in
the stability of individual CYP enzymes from different liver donors,
particularly for the most rapidly declining CYP enzymes. Similar losses
of CYP enzymes were found when human liver slices were cultured in
supplemented Williams' medium E for 72 h, except that CYP2E1
apoprotein levels were better maintained. Because of the variable
decreases of CYP enzymes, xenobiotic metabolism studies are best
performed with freshly cut rather than cultured human liver slices.
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