Toxicologic and immunologic evaluations of N-(all-trans-retinoyl)-DL-leucine and N-(all-trans-retinoyl)glycine

Sprague-Dawley rats were dosed by gavage daily for 28 days with 5, 15, or 50 mg/kg of N-(all-trans-retinoyl)-DL-leucine (RL), N-(all-trans-retinoyl)glycine (RG), or all-trans-retinoic acid (RA). On the basis of mortality incidence, fracture incidence, body weight, and histopathologic effects, RG was slightly to moderately less toxic than RA, and RL was significantly less toxic than RA or RG. Doses that had no effect on weight loss and produced no bone fractures were approximately 5 and 15 mg/kg/day for RA administered to males or females, respectively; greater than 15 mg/kg/day for RG administered to males or females; and greater than 50 mg/kg/day for RL administered to males or females. At these doses, RA and RG produced effects, detectable at the microscopic level, of lymphoid hyperplasia and hematopoietic cell proliferation in the spleen, lymphoid hyperplasia in lymph nodes, necrosis of the cortex of the thymus, hypertrophy of the zona fasciculata of the adrenal, a periportal pattern of cytoplasmic vacuolization in hepatocytes, hematopoietic cell proliferation in the liver, epithelial hyperplasia and subacute inflammation in the forestomach, and osteodystrophy. Serological alterations consisted of reduced serum albumin levels and elevated levels of triglycerides and alkaline phosphatase. For RL, similar microscopic effects, dependent on dose level and sex, were observed in spleen, thymus, adrenal, and liver. In vitro, RL was as active as RA in potentiating pokeweed mitogen-induced lymphocyte proliferation; RG was inactive. This study indicates that, relative to RA and RG, RL has less toxicity but similar immunological effects. Since RL and RG expressed little or no binding affinity for cellular RA-binding protein, the immunological effects of these retinoids may be expressed by mechanisms not linked to this protein.