Effects of oltipraz and related chemoprevention compounds on gene expression in rat liver.
One promising approach to cancer chemoprevention involves the induction of phase II xenobiotic metabolism enzymes. Since this approach requires drugs specifically intended to alter tissue gene expression patterns over long periods, it will be important to determine experimentally which proteins are increased or decreased by treatment, and how such alterations may (or may not) be related to the postulated chemopreventive mechanism. We have employed two-dimensional electrophoresis to detect and quantitate gene expression effects of candidate chemoprevention compounds in the livers of treated rats. Oltipraz, an inducer of several phase II enzymes, affected a series of at least 26 proteins, most of which were slightly decreased by treatment. Several proteins were increased, the prime example being rat liver spot 693, which was induced more than 7-fold by oltipraz. This protein was excised from multiple 2-D gels and subjected to in situ tryptic digestion followed by microchemical sequence analysis. The resulting multiple peptide sequences match perfectly with the cDNA-derived sequence of rat aflatoxin B1 aldehyde reductase (AFAR). Using quantitative measurements of AFAR from 2-D gels, we compared a series of dose regimens. Oltipraz administration by gavage or in diet appeared equally effective, while recovery studies indicated a half-time of 5.5 days for disappearance of the AFAR protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Large Scale Biology Corporation, Rockville, MD 20850, USA.
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L
Anderson
V K
VK
Steele
G J
GJ
Kelloff
S
S
Sharma
D000595:Amino Acid Sequence; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D015415:Biomarkers; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz