Inoculation of human tumor cells alters the basal expression but not the inducibility of cytochrome P450 enzymes in tumor-bearing mouse liver.
The athymic nude mouse is often used to grow tumors for in vivo oncology research, including the identification of anticancer drugs, whereas wild-type mice are usually used to assess the pharmacokinetics (PK) of new chemical entities. The relationship between PK and pharmacodynamics (PD) provides useful mechanistic information and helps guide of the clinical regimen. The aim of this study was to assess whether the inoculation of human hepatocellular carcinoma cells (PLC/PRF/5) into athymic nude mice alters the expression of genes encoding the drug-metabolizing enzymes and transporters in host liver. The livers from nontumor- and tumor-bearing mice were initially subjected to drug metabolism gene microarray analysis. Microarray analysis indicated that tumor inoculation had little effect on drug metabolism-related genes, including several cytochrome P450s: Cyp1a, Cyp2b, and Cyp3a. This result was further confirmed by reverse transcription-polymerase chain reaction (RT-PCR). However, immunoreactive proteins of Cyp1a, Cyp2b, and Cyp3a were suppressed by tumor inoculation. RT-PCR and Western immunoblotting analysis showed that the inducibility of Cyp1a, Cyp2b, and Cyp3a by 3-methylcholanthrene, phenobarbital, and dexamethasone, respectively, was similar between nontumor- and tumor-bearing mice. These results suggest that inoculation of human tumor cells into athymic nude mice suppresses the expression of certain drug-metabolizing enzymes, which may alter the PK and PD of antitumor drugs.
Sugawara
Michiko
M
Drug Metabolism and Pharmacokinetics Research, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. m-sugawara@hhc.eisai.co.jp
Okamoto
Kiyoshi
K
Kadowaki
Tadashi
T
Kusano
Kazutomi
K
Fukamizu
Akiyoshi
A
Yoshimura
Tsutomu
T
D000818:Animals; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D023041:Xenograft Model Antitumor Assays
D003577:Cytochrome P-450 Enzyme System