Monitoring Cyp2b10 mRNA expression at cessation of 2-year carcinogenesis bioassay in mouse liver provides evidence for a carcinogenic mechanism devoid of human relevance: The dalcetrapib experience

被引：12

作者：

Haack, J-C. ^{[1
]}

Mueller, L. ^{[1
]}

Fowler, S. ^{[1
]}

Braendli-Baiocco, A. ^{[1
]}

Flint, N. ^{[1
]}

Kuhlmann, O. ^{[1
]}

Singer, T. ^{[1
]}

Roth, A. ^{[1
]}

机构：

[1] F Hoffmann La Roche Ltd, Pharma Res & Early Dev, Nonclin Drug Safety, PNPL,Nonclin Safety, CH-4070 Basel, Switzerland

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2012年 / 259卷 / 03期

关键词：

Cyp2b10; CAR; Dalcetrapib; Bioassay; Rodent hepatocarcinogenesis; CONSTITUTIVE ANDROSTANE RECEPTOR; PREGNANE-X-RECEPTOR; NUCLEAR RECEPTOR; ACTIVE/ANDROSTANE RECEPTOR; DRUG-METABOLISM; CROSS-TALK; GENE-EXPRESSION; HEPATIC CYP2B; HUMAN CANCER; BILE-ACID;

D O I：

10.1016/j.taap.2012.01.014

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Introduction: Dalcetrapib is a cholesteryl ester transfer protein (CETP) modulator in clinical assessment for cardiovascular outcome benefits. In compliance with regulatory requirements, dalcetrapib was evaluated in rodent 2-year carcinogenesis bioassays. In the mouse bioassay, male mice demonstrated increased liver weight and statistically increased incidences of hepatocellular adenoma/carcinoma. Hepatic cytochrome p450 (Cyp) 2b10 mRNA induction and increased Cyp2b10 enzyme activity signify activation of hepatic nuclear receptor constitutive androstane receptor (CAR), a widely established promoter of rodent-specific hepatic tumors. We therefore monitored hepatic Cyp2b10 mRNA and its enzyme activity in a subset of dalcetrapib-treated male mice from the bioassay. Methods: Liver samples were obtained from -1/3 of male mice from each dose group including vehicle-controls (mean and earliest study day of death 678 and 459 respectively). Quantitative real time PCR (qRT-PCR) was performed to determine Cyp2b10 mRNA expression and Cyp1a-. Cyp2b10- and Cyp3a-selective activities were monitored. Results: Cyp2b10 mRNA was strongly induced by dalcetrapib with an expected wide inter-individual variation (5-1421-fold). Group average fold-induction versus vehicle-controls showed a dose-related increase from 48-fold (250 mg/kg/day) to 160-fold (750 mg/kg/day), which declined slightly at 2000 mg/kg/day (97-fold). Cyp enzyme activities showed approximate doubling of total Cyp P450 content per milligram protein and a 9-fold increase in Cyp2b10-selective pentoxyresorufin O-dealkylase activity (750 mg/kg/day). Discussion: These data from hepatic Cyp2b10 monitoring are strongly suggestive cif CAR activation by dalcetrapib, a mechanism devoid of relevance towards hepatocarcinogenesis in humans; results show feasibility of Cyp2b10 as a surrogate marker for this mechanism at cessation of a carcinogenesis bioassay. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：355 / 365

页数：11