Differential Regulation of the b,b‐carotene 15,15′‐monooxygenase (BCMO1) Expression by b‐carotene and Retinoic Acid in Human Pulmonary Alveolar Epithelial Cells

Abstract

Vitamin A and its retinoid derivatives are essential for normal differentiation of respiratory epithelium. BCMO1 is the key enzyme in metabolism of the provitamin A carotenoid b-carotene to retinoic acid (RA). Recent evidence suggests RA, the biologically active form of vitamin A, may regulate its production via negative feedback of intestinal BCMO1 activity. This study was conducted to investigate b-carotene metabolism and its effects on the regulation of BCMO1 expression in pulmonary alveolar epithelium. We demonstrate that human alveolar epithelial (A549) cells express BCMO1 and metabolize b-carotene to the several biologically active RA isomers. Exposure of A549 cells to high levels of b-carotene reduces expression of BCMO1 at both the mRNA and protein levels. BCMO1 promoter activity is also decreased by b-carotene in a dosage-dependent manner. Reduced expression of BCMO1 by high levels of b-carotene is associated with decreased cellular levels of RXRa and limited formation of the functional PPAR¦Ã/RXRa heterodimer. Conversely, exposure of A549 cells to all-trans RA (ATRA) modestly increases both promoter activity and expression of BCMO1. These findings suggest that b-carotene and RA differently regulate BCMO1 gene expression in A549 cells via differential molecular mechanisms and may help to explain some adverse effects found in pharmacologic b-carotene lung cancer trials. (NIH HD42174, RR18728)