Identification by differential display of the IF1 inhibitor peptide of ATP synthase/ATPase as a gene inducible in rat liver by pregnenolone 16alpha-carbonitrile.

The synthetic steroid, pregnenolone-16alpha-carbonitrile (PCN), activates hepatic metabolism and elimination of xenobiotics mediated by its interaction with the PXR, a nuclear receptor that binds PCN and such glucocorticoids as dexamethasone (Dex). We used mRNA differential display to define further the domain of genes under the control of PCN/PXR. We found 76 cDNA fragments representing mRNAs differentially expressed in the liver of rats treated with PCN or Dex. Sequence analysis of one of these revealed a PCN induced cDNA fragment as IF1, an inhibitor peptide of ATP synthase/ATPase complex. Northern blot analysis revealed that IF1 was detectable in untreated liver and was induced 2-3 fold following treatment with PCN. IF1 mRNA was not detected in lung, heart, kidney, or testes of control or PCN treated rats. We conclude that IF1 inhibitor peptide is a novel representative of an apparently large set of previously unrecognized genes coordinately controlled by the PCN/PXR system to maintain homeostasis during toxic stress.