Subacute toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide, N-2-hydroxyethyl retinamide, and N-4-hydroxyphenyl retinamide.
The major limitation for continuous administration of natural retinoids for chemoprevention of cancer is their high toxicity; however, synthetic retinamides have the desirable quality of reduced toxicity while retaining most of the biological activity. We have presently evaluated the comparative toxicity of all-trans- and 13-cis-isomers of N-ethyl retinamide (ER), N-2-hydroxyethyl retinamide (HER), and N-4-hydroxyphenyl retinamide (HPR) in mice and rats after po and ip administration. The computed LD90, DL50, and LD10 values for combined sexes of mice following 21 daily doses of the above retinoids were determined. Identical doses of the same retinoid by ip administration produced more toxicity and deaths than by the po route. The 13-cis-isomers exhibited comparatively less toxicity than the corresponding all-trans-isomer. Based on the lethality data, all-trans-retinoic acid was most toxic followed by all-trans-HER greater than all-trans-HPR greater than all-trans-ER. Changes in clinical chemistry and hematological parameters associated with administration of the retinamides include a dose-dependent peripheral anemia evidenced by erythrocytopenia and decreased hemoglobin concentration and packed cell volume. Retinoid treatment also caused increased plasma alkaline phosphatase activity and decreased serum albumin levels. Histopathological changes associated with retinoid administration primarily included liver lesions as characterized by degeneration and enlargement of hepatocytes. The present studies indicate that synthetic retinoids are less toxic than the natural ones.
D000469:Alkaline Phosphatase / Q000097:blood; D000740:Anemia / Q000139:chemically induced; D000818:Animals; D005260:Female; D017313:Fenretinide; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000633:toxicity
D017313:Fenretinide; C009675:vitamin A acid ethylamide; C022147:N-(2-hydroxyethyl)retinamide; D014212:Tretinoin; D000469:Alkaline Phosphatase