The retinotoxic drug 1,5-di-(p-aminophenoxy)pentane inhibits the accumulation of all ll-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-cisretinal 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 =15 times faster than the rate of li-cis-retinal isomerization by itself in these liposomes and O24103 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.The initial event in vertebrate vision involves the photochemical isomerization of the li-cis-retinal Schiff base chromophore ofrhodopsin to its all-trans congener (1, 2). Rhodopsin, activated in this fashion, catalyzes the exchange of GTP for GDP in a G protein, which in turn activates a phosphodiesterase specific for cGMP (3, 4). For vision to proceed, the all-trans-retinal released from rhodopsin must be converted back into ll-cis-retinal, a thermodynamically uphill process (5). The
[3H]-all-trans-Retinol injected intraocularly into rats is processed to [3H]-11-cis-retinal, the visually active retinoid that binds to opsin. After 18 h, virtually all (93%) of the radioactive retinals recovered were in the form of 11-cis-retinal. At earlier times, however, both all-trans- and 13-cis-retinals, the latter being a nonphysiological isomer, were formed. Both of these isomers disappeared concomitant with the formation of 11-cis-retinal. The rise and fall of 13-cis-retinal suggest that this isomer can be converted into 11-cis-retinal either directly or indirectly in vivo and, hence, that the biosynthesis of the latter is nonstereospecific. This hypothesis was verified by showing that in double-labeling experiments [14C]-13-cis-retinol was converted into 11-cis-retinal nearly as well (approximately 70%) as [3H]-all-trans-retinol. These studies show that the biosynthesis of 11-cis-retinal can be nonstereospecific and, hence, that the process may be chemically rather than enzymatically mediated in vivo. In contrast, double-labeling studies with [14C]-9-cis-retinol and [3H]-all-trans-retinol showed that very little, if any, of the 9-cis isomer was processed to 11-cis-retinal in vivo although it did form isorhodopsin. This is consistent with what is known about the relative chemical stabilities of 9-cis-retinoids from model studies. The isomerization of 9-cis-retinoids is much slower than that of their all-trans, 13-cis, or 11-cis congeners. These results are discussed in terms of a possible mechanism for the biosynthesis of 11-cis-retinal in vivo and suggest that the isomerization event need not necessarily be enzyme mediated.
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