retinaldehyde and Lung-Neoplasms

A survey is given concerning recent realizations of importance and metabolism of vitamin A in man and experimental animals. The transport of vitamin A from the small intestine takes place in form of esters by inclusion in chylomicrons and lipoproteins. A higher content in the blood plasma over a longer period evokes toxic effects. In the liver one part of the vitamin A in form of an ester with binding to lipoproteins is accumulated, one part is - according to the need - associated with a vitamin-A-binding protein, which forms complexes with prealbumin molecules and transports the vitamin to the various places of effect. With the help of the receptor proteins the vitamin A is included in the cells, in which it is effective and is transported into the vitamin-A-aldehyde and the vitamin-A-acid. The vitamin A and the vitamin-A-acid are transported into the cell nuclei with the help of receptor-proteins and play a role in the differentiation of the tissues and in the regulation of the synthesis of RNA. When a deficit or an abundance of vitamin A is present in the early phase of pregnancy malformations in the fetuses appear. The vitamin A and structure-similar connections have an inhibiting effect on the development of tumours.

Topics: Animals; Biological Transport; Birds; Carotenoids; Carrier Proteins; Chylomicrons; Congenital Abnormalities; Female; Fishes; Humans; Lipoproteins; Lung Neoplasms; Male; Mammals; Pregnancy; Pregnancy Trimester, First; Retinaldehyde; RNA; Smoking; Tretinoin; Vitamin A; Vitamin A Deficiency

AKR1B10 has been identified as a potential biomarker for human nonsmall cell lung carcinoma and as a tobacco exposure and response gene. AKR1B10 functions as an efficient retinal reductase in vitro and may regulate retinoic acid homeostasis. However, the possibility that this enzyme is able to activate polycyclic aromatic hydrocarbon (PAH) trans-dihydrodiols to form reactive and redox-active o-quinones has not been investigated to date. AKR1B10 was found to oxidize a wide range of PAH trans-dihydrodiol substrates in vitro to yield PAH o-quinones. Reactions of AKR1B10 proceeded with improper stereochemistry, since it was specific for the minor (+)-benzo[a]pyrene-7S,8S-dihydrodiol diastereomer formed in vivo. However, AKR1B10 displayed reasonable activity in the oxidation of both the (-)-R,R and (+)-S,S stereoisomers of benzo[g]chrysene-11,12-dihydrodiol and oxidized the potentially relevant, albeit minor, (+)-benz[a]anthracene-3S,4S-dihydrodiol metabolite. We find that AKR1B10 is therefore likely to play a contributing role in the activation of PAH trans-dihydrodiols in human lung. AKR1B10 retinal reductase activity was confirmed in vitro and found to be 5- to 150-fold greater than the oxidation of PAH trans-dihydrodiols examined. AKR1B10 was highly expressed at the mRNA and protein levels in human lung adenocarcinoma A549 cells, and robust retinal reductase activity was measured in lysates of these cells. The much greater catalytic efficiency of retinal reduction compared to PAH trans-dihydrodiol metabolism suggests AKR1B10 may play a greater role in lung carcinogenesis through dysregulation of retinoic acid homeostasis than through oxidation of PAH trans-dihydrodiols.

Topics: Aldehyde Reductase; Aldo-Keto Reductases; Carcinogens; Carcinoma, Non-Small-Cell Lung; Cells, Cultured; Circular Dichroism; Dihydroxydihydrobenzopyrenes; Humans; Lung Neoplasms; Oxidation-Reduction; Polycyclic Aromatic Hydrocarbons; Retinaldehyde

Delivery of beta-carotene in tetrahydrofuran slowed the growth of NCI-H69 small cell lung cancer cells. Analysis of cells and cellular fractions revealed that beta-carotene-treated cells accumulated beta-carotene as well as some polar metabolites, primarily in the crude nuclei. Cells were grown at 1 x 10(5) cells/ml and treated with 20 microM beta-carotene. Growth monitoring up to 15 days indicated an inverse relationship between the duration of beta-carotene treatment and the rate of cell growth. Reverse-phase high-performance liquid chromatography analysis of treated cells showed the presence of beta-carotene, retinoic acid, retinol, and retinal, with beta-carotene accounting for the major material recovered. When cellular fractions were analyzed for beta-carotene, it was found to be located primarily in the crude nuclei. These results demonstrate that treatment of small cell lung cancer cells with beta-carotene results in a reduced growth of the cells. Further investigation is required to show a direct effect of beta-carotene or its intracellular polar metabolites on these cells. Accumulation of beta-carotene in the nucleus suggests a need for evaluating the nuclear role for beta-carotene.

Topics: Antioxidants; beta Carotene; Carcinoma, Small Cell; Cell Division; Cells, Cultured; Humans; Lung Neoplasms; Retinaldehyde; Tretinoin; Tumor Cells, Cultured; Vitamin A