Gene Expression and DevelopmentParticipation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes
Section snippets
Chemicals
[11,13-3H]ATRA (50–60 Ci/mmol) was obtained from Amrad Pharmacia Biotech Australia. [4-14C]Testosterone (56 mCi/mmol) and [1-14C]lauric acid (56 mCi/mmol) were from Amersham. Torasemide was a gift from Boehringer Mannheim, ketoconazole was from Janssen Pharmaceutica, parathion was from Rhone-Poulenc, and cyclophosphamide was from Farmitalia Carlo Erba; diclofenac and sulfaphenazole were from Ciba-Geigy, and tolbutamide, chlorpropamide, and hydroxytolbutamide were provided by Hoechst
Interindividual variation in ATRA metabolism in human liver
Microsomal fractions were derived from excess tissue that was available after the transplantation of cut-down adult livers into pediatric recipients, or the normal margin adjacent to tumor tissue in patients undergoing hepatic resection. ATRA 4-hydroxylation in these livers varied over an approximate 7-fold range (8.7 to 61 pmol 4-hydroxyATRA formed/mg protein/min; Table 1). The recent drug histories of the donors are also shown in Table 1; some were reported in previous studies 23, 24. Five
Discussion
The results of the present investigation implicate a major role for CYP2C8 and a possible minor role for CYP3A4 in the biotransformation of ATRA in human liver. The Michaelis constants for ATRA 4-hydroxylation in three human hepatic microsomal preparations (9.0 ± 3.4 μM) were quite similar to that exhibited by cDNA-expressed CYP2C8 (6 μM) and different from those mediated by cDNA-expressed CYPs 2C9 and 3A4 (>70 μM). Thus, CYP2C8 supported ATRA 4-hydroxylation most efficiently, with CYP2C9 and
Acknowledgements
This work was supported by grants from the New South Wales Cancer Council and the Australian National Health and Medical Research Council. L. N. was the recipient of a Westmead Hospital Initiating Grant and a postgraduate scholarship from the Gastroenterological Society of Australia. The assistance of staff of the Queensland Liver Transplant Service at Princess Alexandra Hospital and the Australian Liver Transplant Center at Royal Prince Alfred Hospital in the supply of human liver tissue for
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