RT Journal Article
SR Electronic
T1 Molecular Basis for Hepatic Detoxifying Enzyme Induction by 2-(Allylthio)pyrazine in Rats in Comparison with Oltipraz: Effects on Prooxidant Production and DNA Degradation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 667
OP 673
VO 27
IS 6
A1 Kim, Sang Geon
A1 Cho, Min Kyung
A1 Choi, Sung Hee
A1 Kim, Hye Jung
A1 Kwak, Mi Kyong
A1 Kim, Nak Doo
YR 1999
UL http://dmd.aspetjournals.org/content/27/6/667.abstract
AB The expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs) by 2-(allylthio)pyrazine (2-AP), an experimental chemopreventive agent, was investigated in rats. Northern blot analysis revealed that 2-AP caused increases in mEH, rGSTA2/3/5, and rGSTM1/2 mRNA levels. mEH and rGSTA2 proteins were also induced. Molecular basis of the enzyme induction by 2-AP was studied in comparison with oltipraz (Olt). Rats exposed to buthionine sulfoximine, a GSH-depleting agent, before treatment with either 2-AP or Olt exhibited greater increases in the mRNA levels than the individual treatment. Conversely, increases of the mRNAs were prevented by cysteine treatment, indicating that metabolic intermediates or reactive oxygens produced from the agents could be reduced by cysteine. Gel shift analysis revealed that nuclear factor-κB, which is associated with the altered cellular redox state, was not activated by the agents. Effects of these agents on the breakage of φx-174 DNA were compared in vitro. 2-AP effectively reduced the conversion of supercoiled DNA to the open circular form induced by benzenetriol and prevented benzenetriol- and iron-catalyzed degradation of DNA, whereas Olt failed to prevent strand breakage of DNA. These results provided evidence that: 1) 2-AP was effective in elevating the hepatic mEH and GST gene expression in rats, which might be mediated with the production of reactive oxygen species; 2) nuclear factor-κB activation was not involved in the induction of the detoxifying enzymes by either 2-AP or Olt in spite of their production of reactive oxygens in vivo; and 3) the antioxidant effect of 2-AP in vitro differed from that of Olt. The American Society for Pharmacology and Experimental Therapeutics