EFFECTS OF THE GENOTOXIC CARCINOGEN CHROMIUM(VI) ON BASAL AND HORMONE-INDUCIBLE PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE-EXPRESSION IN-VIVO -CORRELATION WITH GLUCOCORTICOID-REGULATED AND DEVELOPMENTALLY-REGULATED EXPRESSION

Previous studies have shown that a number of different genotoxic carci nogens that induce different types of DNA damage preferentially alter the expression of inducible genes in vivo. To investigate further the mechanistic basis for these effects, we examined the effects of the hu man lung carcinogen chromium(Vl) on expression of the hormone-inducibl e cytosolic phosphoenolpyruvate carboxykinase (PEPCK) gene in chick em bryo liver. Chromium(VI) pretreatment had significant effects on both basal and glucocorticoid-inducible PEPCK expression in 14-d-old embryo liver. These effects were principally a result of changes in PEPCK tr anscription. In contrast, treatment with chromium(Vl) 1 h after treatm ent with glucocorticoid had no effect on PEPCK induction, suggesting t hat an early event in the induction process is the target for carcinog en effects. In 16-d-old liver, in which PEPCK expression is no longer responsive to glucocorticoid induction, both basal and inducible PEPCK expression were also refractory to chromium(VI) effects, indicating t hat carcinogen responsiveness is a phenotypic rather than an inherent property of inducible genes and is related to their competence for ind uction. Chromium(VI) had no effect on cAMP induction of PEPCK expressi on, demonstrating that carcinogens target their effects to specific re gulatory pathways. Comparison of the effects of chromium(VI) with thos e of cycloheximide suggests that chromium(VI) targets its effects to a labile, constitutively expressed repressor involved in PEPCK gene reg ulation. (C) 1994 Wiley-Liss, Inc.