ACCELERATED COMMUNICATION Activation by Diverse Xenochemicals of the 51-Base Pair Phenobarbital-Responsive Enhancer Module in the CYP2B10

By extending previous studies of the phenobarbital (PB)-re-sponsive 132-base pair (bp) enhancer sequence in the CYP2B10 gene, we have delimited a 51-bp enhancer element that is fully inducible by PB in mouse primary hepatocytes. Sixteen structurally unrelated phenobarbital-type inducers ac-tivated the 51-bp enhancer element in transient transfection assays. The results thus indicate that most PB-type inducers, if not all inducers, increase the transcription of the CYP2B10 gene by activating this 51-bp element, now designated PB-responsive enhancer module or PBREM. The induction of P450s and other drug-metabolizing en-zymes by xenobiotic chemicals is a common cellular defense mechanism against the toxicity and carcinogenicity of foreign compounds. Inducers can be classified into different groups depending on the subset of P450 genes they activate (Okey, 1990). One of the two major groups, polycyclic aromatic hy-drocarbons and dioxins, consists of xenochemicals that acti-vate the xenobiotic response element of CYP1A genes via the aryl hydrocarbon receptor-mediated mechanism (Hankinson, 1995; Whitlock et al., 1996). The other major group of P450 inducers, typified by PB, consists of a host of structurally diverse xenochemicals that induces a subset of P450 genes within the CYP2A, 2B, 2C, and 3A subfamilies, with the CYP2B genes being most effectively up-regulated (Okey