Cell Type-specific Expression of β-Carotene 9', 10'-Monooxygenase in Human Tissues

Abstract

S U M M A R YThe symmetrically cleaving ␤ -carotene 15,15 Ј -monooxygenase (BCO1) catalyzes the first step in the conversion of provitamin A carotenoids to vitamin A in the mucosa of the small intestine. This enzyme is also expressed in epithelia in a variety of extraintestinal tissues. The newly discovered ␤ -carotene 9 Ј ,10 Ј -monooxygenase (BCO2) catalyzes asymmetric cleavage of carotenoids. To gain some insight into the physiological role of BCO2, we determined the expression pattern of BCO2 mRNA and protein in human tissues. By immunohistochemical analysis it was revealed that BCO2 was detected in cell types that are known to express BCO1, such as epithelial cells in the mucosa of small intestine and stomach, parenchymal cells in liver, Leydig and Sertoli cells in testis, kidney tubules, adrenal gland, exocrine pancreas, and retinal pigment epithelium and ciliary body pigment epithelia in the eye. BCO2 was uniquely detected in cardiac and skeletal muscle cells, prostate and endometrial connective tissue, and endocrine pancreas. The finding that the BCO2 enzyme was expressed in some tissues and cell types that are not sensitive to vitamin A deficiency and where no BCO1 has been detected suggests that BCO2 may also be involved in biological processes other than vitamin A synthesis. T he enzymatic action of ␤ -carotene 15,15 Ј -monooxygenases (BCO1) is crucial for the conversion of provitamin A carotenoids to retinol (vitamin A) in the epithelial cells of the small intestine mucosa. The enzyme cleaves the ␤ -ionone ring containing carotenoids centrally, which results in two aldehyde molecules with polyene chains of identical length. Thus cleavage of the most common carotenoid ␤ -carotene results in two molecules of retinaldehyde (retinal), which will be further converted to retinol by a reductive retinal reductase enzyme present in the same cell as BCO1. Previously, we studied the cell type-specific expression of BCO1 and found that the enzyme is also expressed in epithelia of several extraintestinal tissues, which suggested that these tissues have the capacity to directly convert locally stored carotenoids to vitamin A. Thus this may serve as a backup pathway of vitamin A synthesis during times of insufficient dietary intake of preformed vitamin A and provitamin A carotenoids.Recently, Kiefer et al. (2001) cloned and characterized a second carotenoid-cleaving enzyme termed ␤ -carotene 9 Ј ,10 Ј -monooxygenase (BCO2) because it catalyzes asymmetric cleavage of carotenoids, thus yielding one molecule of ␤ -apo-10 Ј -carotenal and one molecule of ␤ -ionone when ␤ -carotene is used as substrate. Interestingly, the BCO2 enzyme appears to accept a wider variety of substrates as compared with BCO1, including the acyclic carotenoid lycopene, which implies that this enzyme may have physiological roles other than providing precursors for vitamin A synthesis.BCO1 and BCO2 belong to a superfamily of nonheme iron-containing oxygenases, many of whose functions are unknown. The physiological role of BCO1 is now well establ...

Mitochondrial β-Carotene 9′,10′ Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function

“…BCO2 is expressed in human normal prostate (21). To determine whether BCO2 is expressed in prostate cancer tissue, we first compared BCO2 protein lysates isolated from normal prostate tissues, benign prostatic hyperplasia (BPH), and prostate cancer tissues by Western blot analysis using an antibody specific for human anti-BCO2 antibody (Fig.…”

“…Expression of the bco1 and bco2 genes overlaps in the human gastrointestinal tract, but bco2, additionally, is expressed in several tissues neither known to be sensitive to vitamin A deficiency nor to express bco1 (20,21). The discovery that BCO1-null mice cannot metabolize b-carotene to vitamin A despite intact bco2 expression (22) implicated BCO2 in biological processes other than vitamin A synthesis.…”

“…BCO2 is expressed in normal prostate epithelium (20,21). The observation that lycopene levels are significantly higher in cancerous than in normal or benign prostate (23) prompted our speculation that BCO2-mediated lycopene metabolism may be impaired in prostate cancer cells.…”

Vertebrate and invertebrate carotenoid-binding proteins

“…Although beta-carotene cleavage activity was demonstrated in cell-free extracts derived from mammalian small intestine in the 1960s, purification of the enzyme proved surprisingly challenging [47][48][49][50]. It was not until the advent of molecular biological approaches and mass spectral sequencing that the beta-carotene cleavage enzyme was cloned first from Drosophila and chicken and later from humans [54][55][56][57][58]. It is a cytosolic enzyme primarily localized in the duodenal mucosa although it has been found in liver and in the eye.…”

“…It has been demonstrated that this enzyme can act on other carotenoids also; however, provitamin A activity might vary depending on the substrate. Cloning of mammalian proteins similar to the 15, 15′ β-carotene oxygenase has revealed the existence of RPE65 [54,56], a protein critical to the cis-trans isomerization of retinoids in the visual cycle, as well as an enzyme that catalyzes the asymmetric cleavage of beta-carotene at the 9′-10′ position [47][48][49]57].…”