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
Cs. Jones et al., 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, Nutrition and cancer, 21(1), 1994, pp. 83-93
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.