Developmental effects of isotretinoin and 4‐oxo‐isotretinoin: The role of metabolism in teratogenicity

Abstract

Previous observations have indicated that isotretinoin (IT), a drug in common use for therapy of cystic acne, is teratogenic in humans but possesses low embryotoxicity in pregnant mice, probably because of its shorter half-life and limited placental transfer in rodents. In human volunteers and patients, one major blood metabolite of IT is 4-oxo-isotretinoin (4-oxo-IT) which undergoes slower elimination than IT and may itself be a participant in teratogenesis. To investigate the problem of species differences displayed by IT and the role of its metabolism, embryotoxic effects of 4-oxo-IT were examined after its single or repeated intubations into pregnant ICR mice and compared with the effects of a similar regimen of IT. The two compounds were also tested for their relative ability to suppress chrondrogenesis in the in vitro cell and organ culture assays. We found that a single dose of 4-oxo-IT, 100 mg/kg, given on day 11 of gestation (plug day = day 0 of gestation) produced a moderate incidence of limb reduction defects and cleft palate (39% and 27% of surviving fetuses, respectively), while a dose of 150 mg/kg affected virtually every fetus. IT, on the other hand, produced no defects in fetuses exposed to similar dose levels. Repeated intubations with IT, however, resulted in increasing the frequencies of limb reduction defects and cleft palate to levels obtained after 4-oxo-IT administration. We found that a 3-hour interval between IT intubations was more effective in this regard than an 8-hour interval. Repeated IT intubations also uncovered sharper stage-dependency of limb and palatal defects than obtained otherwise.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure-activity relationships of retinoids in developmental toxicology

“…At present it is unknown to what extent the oxidized, teratogenic metabolites contribute to the embryotoxicity of all-J..[llm-RA and 13-lli-retinoic acid (13-lli-RA, isotretinoin). These observations are consistent with those of Goulding and Pratt (1986), Webster et al (1986), and Kochhar and Penner (1987), who found the 4-oxo metabolite of 13-ill-RA equipotent to 13-ill-RA in intact pregnant ICR or C57 Bl/6J mice, cultured CO-l mouse embryos, cultured CFHB rat embryos, and cultured ICR mouse forelimb buds. 4-0xoretinoic acid was nearly as active as all-trans-RA in the hamster tracheal organ culture assay (4-oxoretinoic acid ED50 = 700 pM; all-J..[llm-RA ED50 = 30 pM) (Newton et al, 1980).…”

Retinoid-Induced Epiphyseal Plate Closure in Guinea Pigs

“…Cartilage-specific proteoglycan is a marker of the differentiated phenotype of chondrocytes (Benya and Padilla, 1986). Retinoids are also known to inhibit chondrogenesis in cell culture systems (Kochar and Penner, 1987;Eckhardt and Schmitt, 1994). Thus, a direct effect of retinoids on the differentiation state of chondrocytes could be an important mechanistic component of retinoid-induced epiphyseal plate closure.…”

Effect of Retinoids on Proliferation of Human Embryonic Palatal Mesenchymal Cells in Culture

“…?_), has been utilized for the treatment of dermatologic disorders since 1982 (8). Retinoic acids have been reported to produce multiple abnormalities including limb deformities, heart de fects, and facial malformations in mammals and have similar teratogenic effects in humans (9)(10)(11)(12)(13).…”