Short-circuiting the visual cycle with retinotoxic aromatic amines.
The retinotoxic drug 1,5-di-(p-aminophenoxy)pentane inhibits the accumulation of all 11-cis-retinoids in the eye and can deplete preformed stores of them. It is shown here that these effects are not specific to 1,5-di-(p-aminophenoxy)pentane but are shared generally by primary aromatic amines containing a hydrophobic tail. Furthermore, certain clinically used drugs, such as the anti-inflammatory drug phenacetin, can be metabolized to produce these retinotoxic amines. It is likely that hydrophobic aromatic amines will in general be retinotoxic, and drugs based on these structures need to be reassessed in this light. It is proposed here that these amines function by catalyzing the isomerization of 11-cis-retinal thermodynamically downhill to form its all-trans congener. This mechanism accounts for the lack of structural specificity observed with these compounds and is supported by experimental evidence presented here. Schiff bases formed between 11-cis-retinal and a relevant aromatic amine in phosphatidylcholine-based liposomes lead to the formation of the all-trans isomer, at rates approximately equal to 15 times faster than the rate of 11-cis-retinal isomerization by itself in these liposomes and 10(2)-10(3) times faster than the rate of isomerization of this molecule in n-heptane. The rates of the amine-catalyzed isomerization are fast enough to account for their in vivo effect.
D000588:Amines / Q000633:toxicity*; D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D007536:Isomerism; D010777:Photochemistry; D011894:Rana pipiens; D012160:Retina / Q000187:drug effects*; D012168:Retinal Pigments / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism*; D012243:Rhodopsin / Q000378:metabolism*; D012545:Schiff Bases / Q000378:metabolism; D013329:Structure-Activity Relationship
D000588:Amines; D000814:Aniline Compounds; D012168:Retinal Pigments; D012176:Retinoids; D012545:Schiff Bases; C000900:1,5-bis(p-aminophenoxy)pentane; D012243:Rhodopsin