Jones C S, Sly L, Chen L C, Ben T, Brugh-Collins M, Lichti U, De Luca L M
Differentiation Control Section, National Cancer Institute, Bethesda, MD 20892.
Nutr Cancer. 1994;21(1):83-93. doi: 10.1080/01635589409514306.
Using 7,12-dimethylbenz[a]anthracene as the initiator and 12-O-tetradecanoyl-13-acetate as the tumor promoter on the dorsal skin of Sencar mice, we previously showed that pharmacological dietary all-trans-retinoic acid and beta-carotene inhibit the conversion of papillomas to carcinomas in a two-stage system of chemical carcinogenesis. The purpose of this study was to determine the influence of dietary retinoic acid and beta-carotene on retinoid and beta-carotene concentrations in skin and other tissues. We were unable to measure tissue retinoic acid because of the relatively limited amount of tissue available for analysis and the fast rate of metabolism. Different dietary levels of retinoic acid or beta-carotene did not influence total retinol of skin, papilloma, and carcinoma tissues, which all showed a concentration of approximately 1 +/- 0.5 microgram/g wet wt. Equally refractory to dietary retinoic acid or beta-carotene was serum retinol concentration. In contrast, dietary retinoic acid protected loss of liver retinol and retinyl palmitate, and beta-carotene caused an increase in beta-carotene and retinyl palmitate in liver but did not affect serum and liver retinol. We further investigated metabolic and functional aspects of retinoic acid in cultured mouse epidermal keratinocytes (LC-8 cells) and found that these cells actively metabolized [10,11-14C]retinoic acid to polar compounds. Isomers of retinoic acid were a minor product in the presence of cells and the major product when incubated in serum-containing medium in the absence of cells. From the functional point of view, exposure of LC-8 cells to 3 x 10(-6) M all-trans-retinoic acid (RA) caused a 75-fold induction in tissue transglutaminase and an approximately 9-fold induction in 10(-6) M RA at three days of culture. We conclude that retinoic acid spares endogenous retinol and that beta-carotene greatly enhances liver retinyl palmitate levels. Moreover we show that although mouse epidermal cells metabolize retinoic acid at a very high rate, they respond functionally by induction of tissue transglutaminase activity. Because this enzyme has been suggested to be involved in programmed cell death, we are presently investigating the possibility that it may be involved in the inhibition of carcinogenesis in mice fed pharmacological doses of RA.
以7,12 - 二甲基苯并[a]蒽为引发剂，12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯为促癌剂，作用于Sencar小鼠背部皮肤，我们先前的研究表明，在化学致癌的两阶段系统中，药理剂量的膳食全反式维甲酸和β - 胡萝卜素可抑制乳头状瘤向癌的转化。本研究的目的是确定膳食维甲酸和β - 胡萝卜素对皮肤及其他组织中类视黄醇和β - 胡萝卜素浓度的影响。由于可供分析的组织量相对有限且代谢速率较快，我们无法测量组织中的维甲酸含量。不同膳食水平的维甲酸或β - 胡萝卜素对皮肤、乳头状瘤和癌组织中的总视黄醇没有影响，这些组织中的视黄醇浓度均约为1±0.5微克/克湿重。血清视黄醇浓度对膳食维甲酸或β - 胡萝卜素同样不敏感。相比之下，膳食维甲酸可防止肝脏视黄醇和视黄醇棕榈酸酯的流失，β - 胡萝卜素可使肝脏中的β - 胡萝卜素和视黄醇棕榈酸酯增加，但不影响血清和肝脏中的视黄醇。我们进一步研究了培养的小鼠表皮角质形成细胞（LC - 8细胞）中维甲酸的代谢和功能方面，发现这些细胞可将[10,11 - 14C]维甲酸快速代谢为极性化合物。在有细胞存在的情况下，维甲酸异构体是次要产物，而在无细胞的含血清培养基中孵育时则是主要产物。从功能角度来看，将LC - 8细胞暴露于3×10−6 M的全反式维甲酸（RA）中，在培养三天时可使组织转谷氨酰胺酶诱导增加75倍，在10−6 M RA时诱导增加约9倍。我们得出结论，维甲酸可节省内源性视黄醇，β - 胡萝卜素可显著提高肝脏视黄醇棕榈酸酯水平。此外，我们表明，尽管小鼠表皮细胞以非常高的速率代谢维甲酸，但它们通过诱导组织转谷氨酰胺酶活性在功能上做出反应。由于该酶被认为与程序性细胞死亡有关，我们目前正在研究它是否可能参与了给小鼠喂食药理剂量的RA后对致癌作用的抑制。
