Differential display in rat livers treated for 13 weeks with phenobarbital implicates a role for metabolic and oxidative stress in nongenotoxic carcinogenicity.
Hepatic enzyme inducers such as phenobarbital are often nongenotoxic rodent hepatocarcinogens. Currently, nongenotoxic hepatocarcinogens can only be definitively identified through costly and extensive long-term, repeat-dose studies (e.g., 2-year rodent carcinogenicity assays). Although liver tumors caused by these compounds are often not found to be relevant to human health, the mechanism(s) by which they cause carcinogenesis are not well understood. Toxicogenomic technologies represent a new approach to understanding the molecular bases of toxicological liabilities such asnongenotoxic carcinogenicity early in the drug discovery/development process. Microarrays have been used to identify mechanistic molecular markers of nongenotoxic rodent hepatocarcinogenesis in short-term, repeat-dose preclinical safety studies. However, the initial "noise" of early adaptive changes may confound mechanistic interpretation of transcription profiling data from short-term studies, and the molecular processes triggered by treatment with a xenobiotic agent are likely to change over the course of long-term treatment. Here, we describe the use of a differential display technology to understand the molecular mechanisms related to 13 weeks of dosing with the prototype rodent nongenotoxic hepatocarcinogen, phenobarbital. These findings implicate a continuing role for oxidative stress in nongenotoxic carcinogenicity.An Excel data file containing raw data is available in full at http://taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233. Click on the issue link for 33(1), then select this article. A download option appears at the bottom of this abstract. The file contains raw data for all gene changes detected by AFLP, including novel genes and genes of unknown function; sequences of detected genes; and animal body and liver weight ratios. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.
Elrick
Mollisa M
MM
Pfizer Corporation, Worldwide Safety Sciences, St Louis, Missouri 63167, USA. mollisa.m.elrick@pfizer.com
Kramer
Jeffrey A
JA
Alden
Carl L
CL
Blomme
Eric A G
EA
Bunch
Roderick T
RT
Cabonce
Marc A
MA
Curtiss
Sandra W
SW
Kier
Larry D
LD
Kolaja
Kyle L
KL
Rodi
Charles P
CP
Morris
Dale L
DL
D000818:Animals; D015870:Gene Expression / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology*; D018384:Oxidative Stress / Q000187:drug effects*; D010634:Phenobarbital / Q000633:toxicity*; D012150:Polymorphism, Restriction Fragment Length; D051381:Rats; D011919:Rats, Inbred Strains; D023382:Toxicity Tests, Acute
D010634:Phenobarbital