Correlation between the results of in vitro and in vivo chromosomal damage tests in consideration of exposure levels of test chemicals.

Introduction: We examined the correlation between the results of in vitro and in vivo chromosomal damage tests by using in-house data of 18 pharmaceutical candidates that showed positive results in the in vitro chromosomal aberration or micronucleus test using CHL/IU cells, and quantitatively analyzed them especially in regard to exposure levels of the compounds.

Findings: Eight compounds showed that the exposure levels [maximum plasma concentration (C) and AUC] were comparable with or higher than the in vitro exposure levels [the lowest effective (positive) concentration (LEC) and AUC = LEC (μg/mL) × treatment time (h)]. Among them, 3 compounds were positive in the in vivo rodent micronucleus assays using bone marrow cells.

The suitability of rat hepatoma cell line H4IIE for evaluating the potentials of compounds to induce CYP3A23 expression.

To investigate the suitability of H4IIE cells for detecting cytochrome P450 (CYP) induction in vitro, we compared CYP induction by typical CYP inducers in H4IIE cells and rat primary hepatocytes by examining gene expression and enzyme activity, and by immunocytochemistry. The cells were preincubated with 0.1 μM of dexamethasone (DEX) for 24 h, followed by 48 h of exposure to 10 μM of beta-naphthoflavone (bNF), 100 μM of phenobarbital (PB) and 10 μM of DEX.

Evaluation of a liver micronucleus assay in young rats (III): a study using nine hepatotoxicants by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study Group (MMS).

We have been investigating a liver micronucleus assay to detect genotoxic chemicals using young rats for several years, and had established its advantages with respect to using autonomous proliferation of young rat hepatocytes. Nine chemicals known to induce hepatotoxic effects such as necrosis (2,6-dinitrotolune, bromobenzene, isoniazid, phenacetin, allyl alcohol and thioacetamide), cholestasis (chlorpromazine hydrochloride and alpha-naphthyl isothiocyanate) and oxidative stress (clofibrate) were selected for this study. A liver micronucleus assay was conducted in 4-week-old male F344 rats using two or three dose levels of test chemicals given orally by gavage to evaluate the compound's ability to induce micronucleated hepatocytes.

Characterization and interlaboratory comparison of a gene expression signature for differentiating genotoxic mechanisms.

The genotoxicity testing battery is highly sensitive for detection of chemical carcinogens. However, it features a low specificity and provides only limited mechanistic information required for risk assessment of positive findings. This is especially important in case of positive findings in the in vitro chromosome damage assays, because chromosome damage may be also induced secondarily to cell death.

Morphological and gene expression analysis in mouse primary cultured hepatocytes exposed to streptozotocin.

Streptozotocin (SZ) is known to exert toxic effects not only on pancreatic islet beta cells but also on other organs including the liver. For analyzing direct effects of SZ on hepatocytes, we performed morphological analysis and DNA microarray analysis on mouse primary cultured hepatocytes. Hepatocytes were taken from non-treated Crj:CD-1(ICR) mice.

Gene expression profiling in streptozotocin treated mouse liver using DNA microarray.

Streptozotocin (SZ) is known to exert toxic effects not only on pancreatic islet beta cells but also on other organs including liver. For analyzing changes in genes expression associated with SZ toxicity, we performed DNA microarray analyses on the liver obtained from SZ-treated mice. Eight-week-old male ICR mice were treated i.

Hepatic changes in the acute phase of streptozotocin (SZ)-induced diabetes in mice.

We have reported the streptozotocin (SZ)-induced hepatic lesions in the subacute phase (4 to 12 weeks after the treatment), which are characterized by appearance of oncocytic hepatocytes, cytomegalic hepatocytes and bile duct hyperplasia. In this study, we focused on the acute phase (6 to 48 hours after the treatment) of the SZ-induced hepatic lesions of mice to clarify the onset of the hepatic alterations, especially before the induction of hyperglycemia. Livers were taken from 8-week-old Crj:CD-1 (ICR) male mice at 6, 12, 24, 36 and 48 hours after the 200 mg/kg b.