Comparative disposition, receptor affinity, and teratogenic activity of sulfon arotinoids.
To investigate the relationship between sulfon arotinoid biotransformation and teratogenic activity, the potency of the ethyl (Ro 15-1570) and methyl (Ro 14-9706) arotinoid sulfones and their in vivo disposition in pregnant hamsters were studied. Administration of Ro 15-1570 was teratogenic, but Ro 14-9706 showed no such activity. Total absorbed doses of the ethyl and methyl sulfones (measured as maternal plasma AUC) were very similar. Total delivered dose of Ro 14-9706 to liver and lung was 120-160% that of Ro 15-157, and Ro 14-9706 was transferred in greater amounts to the embryo as well. Placenta AUC for parent sulfon arotinoids was 160-250% that in the embryo. Plasma analyses by HPLC suggested that the ethyl sulfone was oxidized and appeared in maternal plasma as the corresponding sulfinic (Ro 14-9572) and sulfonic (Ro 14-3899) acids, amounting to 10% and 16%, respectively, of the mean maternal ethyl sulfone Cmax value. The concentrations of sulfinic and sulfonic metabolites were always less than the analytical limit of detection in placenta and embryo after maternal ethyl sulfone intubation. Neither the sulfinic nor the sulfonic acid were ever detected in maternal circulation, placenta, or embryo after methyl sulfone intubation. Comparisons of their binding affinities found that neither the ethyl nor the methyl arotinoid sulfone could act as a ligand for cellular retinoic acid-binding protein (CRABP), nor could these compounds bind retinoid nuclear receptors (RAR). Transcriptional activation of RARs was weak and similar for both compounds. The sulfinic and sulfonic acid arotinoids bind and transactivate RARs, and bind CRABP with efficiencies similar to all-trans-retinoic acid. Furthermore, they are active in cultured limb bud chondrocytes. The results suggest that the methyl sulfone (in accord with its lack of activity in cultured limb bud chondrocytes) is of no toxicologic significance in hamster embryo--even after relatively high delivered dose. Teratogenicity of the ethyl sulfone (which shows marked inhibition of chondrogenesis in cultured limb bud) does not appear to depend on measurable concentrations of these sulfinic/sulfonic acid metabolites in the hamster embryo.
Willhite
C C
CC
Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA.
Dubois
A
A
Schindler-Horvat
J
J
Apfel
C
C
Eckhoff
C
C
D000014:Abnormalities, Drug-Induced / Q000503:physiopathology*; D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D016001:Confidence Intervals; D006224:Cricetinae; D004622:Embryo, Mammalian / Q000737:chemistry; D005260:Female; D018878:Limb Buds / Q000002:abnormalities; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000493:pharmacokinetics / Q000633:toxicity*; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013450:Sulfones; C045042:Ro 15-1570; C069613:sumarotene