pA2 online
Copyright 2004 The British Pharmacological Society

225P GKT, University of London
Winter Meeting December 2003

Abundance of cytochromes P450 in human liver: a meta-analysis

K. Rowland Yeo1, A. Rostami-Hodjegan1,2& G. T. Tucker2. 1Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU, UK and 2Molecular Pharmacology & Pharmacogenetics, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.

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Rowland-Yeo K
Rostami-Hodjegan A
Tucker GT

Recombinant systems expressing human cytochrome P450 isoforms (rCYP) are used in vitro for rapid screening for metabolic activity as well as for in vitro in vivo extrapolations (IVIVE) [1]. However, abundances of the respective enzymes in human liver are needed to correct for the relative contribution of each enzyme to the total metabolism. Shimada et al. (1994) is the most cited source for the latter information [914 citations in ISI database (September, 2003)] despite the fact that the study was based on liver samples from only 30 Japanese and 30 Caucasian subjects [2]. Therefore, the aim of our study was to derive abundance values for individual CYPs using all available data (19 sources).

Two electronic data bases MEDLINE and BIDS EMBASE, and personal files (1990-2003) containing references from Current Contents and Reference Update were searched for the pertinent literature using appropriate key words. Authors were contacted directly when further information was required. Only human liver data from Caucasians were included and the source was identified to ensure that none were duplicated in the analyses. For each isoform, abundance values were tested for homogeneity and shape of the distribution. Following calculation of the weighted mean, standard deviation and coefficient of variation (CV) [3], the geometric mean (GM) and the geometric standard deviation were derived assuming a log-normal distribution [4].

Table Abundance of CYPs (pmol P450 mg-1 protein) in human liver determined from a meta-analysis of all reported data and those cited by by Shimada et al (1994).

Meta-analysis
Shimada
All (n=60)
Caucasian (n=30)
Mean
GM
CV
Mean
GM
CV
Mean
GM
CV
1A2
52
37
67
42
37
55
58
53
47
2A6
36
29
84
14
10
93
23
19
73
2B6
11
7
147
1
1
200
2
1
86
2C
-
-
-
60
55
45
77
72
35
2C8
24
19
81
-
-
-
-
-
-
2C9
73
60
54
-
-
-
-
-
-
2C19
14
9
106
-
-
-
-
-
-
2D6
8
7
61
5
4
80
9
7
62
2E1
61
49
61
22
19
55
27
24
46
3A
155
131
67
96
85
53
120
114
35

Abundances derived for each of the isoforms in this study and those reported by Shimada et al. [2] are shown in the table. With the exception of CYP1A2 and CYP2D6, mean values from the meta-analysis appear to be greater. The values reported in our study are based on 42 to 241 liver samples and therefore may give a more realistic representation of CYP abundance and its variability in the Caucasian population than those reported [2] and cited frequently by many research groups. In view of the possible differences between Japanese and Caucasians [2] a meta-analysis similar to the one presented here is warranted to derive abundance values for the Japanese population and possibly other ethnic groups.

1. Proctor NJ, et al. Xenobiotica (in press).
2. Shimada T, et al. (1994) J Pharmacol Exp Ther 270: 414-423.
3. Armitage M, et al. (2002) Statistical methods in Medical Research, 4th Oxford, Blackwell Science, 309-311.
4. Aitchison and Brown, (1996) The log-normal distribution, University Press, Cambridge.