Reversal by retinoids of keratinization induced by benzo[alpha]pyrene in normal hamster tracheal explants: comparison with the assay involving organ culture of tracheas from vitamin A-deficient hamsters.
In a defined culture system for hamster tracheal explants, the activity of 12 different retinoids was evaluated for reversal of keratinization induced by exposure to the carcinogen, benzo[alpha]pyrene (BP-HTOC assay). The effects of retinoids in this system were compared to those in a defined culture system for tracheal explants from vitamin A-deficient hamsters (standard-HTOC assay). In both assays, all-trans-retinoic acid (RA) and 13-cis-RA were the most active retinoids. For RA and 13-cis-RA, the values of ED50 determined in the BP-HTOC bioassay were 4 x 10(-12) and 1 x 10(-11) M, respectively, whereas the corresponding values in the standard HTOC assay were 2 x 10(-11) and 3.3 x 10(-10) M. For all 12 retinoids, the ED50 values from the BP-HTOC were lower than those from the standard-HTOC assay, and there was also a statistically significant correlation between the rank-ordering of ED50 values from the 2 assays. Among 3 N-(retinoyl)amino acids examined in both assays, N-(retinoyl)leucine was the most active, N-(retinoyl)phenylalanine the least active, and N-(retinoyl)alanine intermediate. Among a novel series of bifunctional retinoic acid analogues, the dicarboxyl derivative was the most active. On the basis of these results, the BP-HTOC assay appears to be one of the most sensitive assays for retinoids yet developed. This assay is an appropriate model for evaluating the chemopreventive potential of new retinoids in vitro.
Wille
J J
JJ
Kettering-Meyer Laboratoires, Southern Research Institute, Birmingham, AL 35255.
Chopra
D P
DP
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D006224:Cricetinae; D046508:Culture Techniques; D004848:Epithelium / Q000187:drug effects; D007633:Keratins / Q000096:biosynthesis*; D008647:Mesocricetus; D008679:Metaplasia / Q000139:chemically induced; D012176:Retinoids / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014802:Vitamin A Deficiency / Q000378:metabolism
D012176:Retinoids; D001564:Benzo(a)pyrene; D007633:Keratins