Effects of oltipraz and related chemoprevention compounds on gene expression in rat liver

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Abstract
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. Oltipraz analogs anethole trithione (ANTT), 1,2-dithiole-3-thione (1,2-DT-3-T) and 1,3-dithiole-2-thione (1,3-DT-3-T) were examined with respect to ability to increase liver AFAR levels: ANTT appeared approximately equipotent with oltipraz, 1,2-DT-3-T appeared more than 10 times as potent, and 1,3-DT-2-T did not significantly induce AFAR, while nevertheless causing significant changes in a distinct set of proteins. This latter set was shown, by multivariate statistical comparison with an extended set of chemoprevention compounds, to closely resemble the effects of piroxicam at high dose.

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