RETINOL AND BETA-CAROTENE CONCENTRATIONS IN SKIN, PAPILLOMAS AND CARCINOMAS, LIVER, AND SERUM OF MICE FED RETINOIC ACID OR BETA-CAROTENE TOSUPPRESS SKIN TUMOR-FORMATION

Using 7,12-dimethylbenz[a]anthracene as the initiator and 12-O-tetrane canoyl-13-acetate as the tumor promoter on the dorsal skin of Sencar m ice, we previously showed that pharmacological dietary all-trans-retin oic acid and p-carotene inhibit the conversion of papillomas to carcin omas in a two-stage system of chemical carcinogenesis. The purpose of this study was to determine the influence of dietary retinoic acid and p-carotene on retinoid and beta-carotene concentrations in skin and o ther tissues We were unable to measure tissue retinoic acid because of the relatively limited amount of tissue available for analysis and th e fast rate of metabolism. different dietary levels of retinoic acid o r p-carotene did not influence total retinol of skin, papilloma, and c arcinoma tissues, which all showed a concentration of approximately 1 +/- 0.5 mu g/g wet wt. Equally refractory To dietary retinoic acid or p-carotene was serum retinol concentration. In contrast, dietary retin oic acid protected loss of liver retinol and retinyl palmitate, and p- carotene caused an increase in p-carotene and retinyl palmitate in liv er but did not affect serum and liver retinol. We further investigated metabolic and functional aspects of retinoic acid in cultured mouse e pidermal keratinocytes (LC-8 cells) and found that these cells activel y metabolized [10,11-C-14]retinoic acid to polar compounds. Isomers of retinoic acid were a minor product in the presence of cells and the m ajor 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 i n tissue transglutaminase and an approximately 9-fold induction in 10( -6) M R4 at three days of culture. We conclude that retinoic acid spar es endogenous retinol and that beta-carotene greatly enhances liver re tinyl palmitate levels. Moreover we show that although mouse epidermal cells metabolize retinoic acid at a very high rate, they respond func tionally by induction of tissue transglutaminase activity. Because thi s enzyme has been suggested to be involved in programmed cell death, w e are presently investigating the possibility that it may be involved in the inhibition of carcinogenesis in mice fed pharmacolagical doses of RA.