A proposed mechanism for p-aminoclonidine allergenicity based on its relative oxidative lability.
p-Aminoclonidine (apraclonidine) is a selective alpha 2 adrenergic agonist used to reduce intraocular pressure in the treatment of glaucoma. Use of apraclonidine is frequently associated with severe local allergic effects which warrant discontinuation of the drug in affected patients. We have assessed the oxidative lability of apraclonidine relative to a panel of adrenergic agonists and/or known allergens; amodiaquine, epinephrine, clonidine, and brimonidine. These compounds were compared by their electrochemical potentials as well as their oxidative lability in the presence of several oxidative enzyme systems (i.e., horseradish peroxidase, lactoperoxidase, myeloperoxidase, and diamine oxidase). The half-lives for enzymatic oxidation of these compounds were found to parallel the electrochemical oxidation potentials in the order: amodiaquine approximately epinephrine < apraclonidine << clonidine approximately brimonidine. The production of a reactive electrophilic intermediate of apraclonidine was demonstrated through the formation of two glutathione apraclonidine adducts from the horseradish peroxidase/H2O2-mediated oxidation of apraclonidine in the presence of glutathione. A mechanism for apraclonidine allergenicity in vivo is proposed wherein apraclonidine is bioactivated through oxidation to the bis-iminoquinone followed by protein conjugation to form an apraclonidine-protein hapten that elicits the immune response.
Thompson
C D
CD
Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Vachaspati
P R
PR
Kolis
S P
SP
Gulden
P H
PH
Garst
M E
ME
Wiese
A
A
Munk
S A
SA
Harman
W D
WD
Macdonald
T L
TL
D000316:Adrenergic alpha-Agonists / Q000737:chemistry* / Q000633:toxicity*; D000485:Allergens / Q000737:chemistry* / Q000633:toxicity*; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D004563:Electrochemistry; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D006735:Horseradish Peroxidase / Q000378:metabolism; D007784:Lactoperoxidase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000485:Allergens; C016986:apraclonidine; D006735:Horseradish Peroxidase; D007784:Lactoperoxidase; D009195:Peroxidase; D006631:Amine Oxidase (Copper-Containing); D005978:Glutathione; D003000:Clonidine