Regulation of flavin-containing monooxygenase 1 expression by Ying Yang 1 and hepatic nuclear factors 1 and 4

The flavin-containing monooxygenases (FMOs) are important for the oxidation of a variety of environmental toxicants, natural products, and therapeutic s. Consisting of six family members (FMO1-5), these enzymes exhibit distinc t but broad and overlapping substrate specificity and are expressed in a hi ghly tissue- and species-selective manner. Corresponding to previously iden tified regulatory domains, a YY1 binding site was identified at the major r abbit FMO1 promoter, position -8 to -2, two overlapping HNF1 alpha sites, p osition -132 to -105, and two HNF4 alpha sites, position -467 to -454 and - 195 to -182. Cotransfection studies with HNF1 alpha and HNF4 alpha expressi on vectors demonstrated a major role for each of these factors in enhancing FMO1 promoter activity. In contrast, YY1 was shown by site-directed mutage nesis to be dispensable for basal promoter activity but suppressed the abil ity of the upstream domains to enhance transcription. Finally, comparisons between rabbit and human FMO1 demonstrated conservation of each of these re gulatory elements. With the exception of the most distal HNF4 alpha site, e ach of the orthologous human sequences also was able to compete with rabbit FMO1 cis-elements for specific protein binding. These data are consistent with these same elements being important for regulating human FMO1 developm ental- and tissue-specific expression.