The intron of the corticotropin-releasing hormone (corticoliberin; CRH) gene contains a sequence of over 100 bp of alternating purine/pyrimidine residues, We have used binding of a Z-DNA-specific antibody in metabolically active, permeabilized nuclei to study the formation of Z-DNA in this sequence at various levels of transcription, In the NPLC human primary liver carcinoma cell line, activation of cAMP-dependent pathways increased the level of transcription, while adding glucocorticoids inhibited transcription of the CRH gene, These cells respond in a manner similar to hypothalamic cells, Z-DNA formation in this sequence was detected at the basal level of transcription, as well as after stimulation with forskolin, Inhibition of transcription by dexamethasone abolished Z-DNA formation, Z-DNA formation in the MYC gene (c-myc) was affected differently in the same experiment, Thus, changes in Z-DNA formation in the CRH gene are gene specific and are linked to the transcription of the gene.