Retinoic Acid Toxicity

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Toxicity of retinoic acid, including changes in body weight

Collins et al 1994 PMID 8048045


Hixson and Denine 1978 PMID 675692

Abstract: “Swiss mice were treated once a day for 21 days with all-trans- or 13-cis-retinoic acid administered ip or po. The LD50 of all-trans-retinoic acid was 31 mg/kg ip and 1100 mg/kg po; the LD50 of 13-cis-retinoic acid was 140 mg/kg ip and 26,000 mg/kg po. However, after 21 consecutive days of treatment, fractured bones were observed in treated animals at all tested doses of 13-cis-retinoic acid and at doses of all-trans-retinoic acid higher than 3 mg/kg ip or 10 mg/kg po. By either route of administration, 13-cis-retinoic acid produced the same number and incidence of fractures at doses three to five times that of all-trans-retinoic acid administered by the same route.… Based on these parameters of toxicity, 13-cis-retinoic acid was less toxic than all-trans-retinoic acid.”

Hixson et al 1979 PMID 452027

“Young adult Sprague-Dawley rats 52 days old and weighing approximately 200 g were treated for 4, 8, or 12 weeks with a daily oral dose of 0.5, 2.0, or 5.0 mg/kg of all-trans-retinoic acid or 4.0, 15.0, or 40.0 mg/kg of 13-cis-retinoic acid. No differences were observed in the percentage of weight gained or in food consumption between treated and control rats… Overt toxicity was not observed after administration of either compound, but 13-cis-retinoic acid may have a greater potential for clinical utility, since higher dosages were tolerated”

Kurtz et al 1984 PMID 6710536

“Sprague-Dawley rats received daily oral gavage doses of … all-trans-retinoic acid (1, 4, 14, or 50 mg/kg) for 13 weeks. Rats given 50 mg/kg of all-trans-retinoic acid developed numerous long-bone fractures and became moribund during the third week of the study. Those receiving lower dosages survived until scheduled termination, but the 14 mg/kg group showed clear signs of retinoid intoxication including growth depression, anemia, serum alkaline phosphatase elevation, bone fracture, and testicular degeneration.”

Ogilvie et al 2004 PMID 14605005

Not sure if RXR agonist is relevant to retinoic acid per se.

LG100268 (LG268), a potent RXR agonist that activates all three receptor subtypes (alpha, beta, and gamma ) 42 days of treatment, daily dose of 30 mg/kg p.o. reduced BW in Zucker rats, 100 mg/kg (p.o.) reduced BW in lean rats. (also decreased plasma insulin, increased triglycerides, decreased T4). Decrease in Zucker rats due to decrease meal size with no change in frequency (conclude therefore it is not aversive). ICV administration (30 µg/rat/day) decreased BW and plasma insulin, but did not increase triglycerides or decrease T4.