Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP). Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias. It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme called phosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase). Since this enzyme is the rate limiting factor for purine synthesis, this alters the synthesis and function of RNA and DNA. Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis. Pharmacogenetics
The enzyme thiopurine S-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-mercaptopurine. TPMT catalyzes the methylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine – this methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites.
Optical coherence tomography (OCT) may also be used to confirm the diagnosis of CRAO. Causes
CRAO can be classified based on it pathogenesis, as arteritic versus non-arteritic. Non-arteritic CRAO is most commonly caused by an embolus and occlusion at the narrowest part of the carotid retinal artery due to plaques in the carotid artery resulting in carotid retinal artery atherosclerosis. Further causes of non-arteritic CRAO may include vasculitis and chronic systemic autoimmune diseases. Arteritic CRAO is most commonly caused by giant cell arteritis. Other causes can include dissecting aneurysms and arterial spasms, and as a complication of patient positioning causing external compression of the eye compressing flow to the central retinal artery (e.g. in spine surgeries in the prone position). Mechanism
The ophthalmic artery branches off into the central retinal artery which travels with the optic nerve until it enters the eye. This central retinal artery provides nutrients to the retina of the eye, more specifically the inner retina and the surface of the optic nerve. Variations, such as branch retinal artery occlusion, can also occur. Central retinal artery occlusion is most often due to emboli blocking the artery and therefore prevents the artery from delivering nutrients to most of the retina. These emboli originate from the carotid arteries most of the time but in 25% of cases, this is due to plaque build-up in the ophthalmic artery. The most frequent site of blockage is at the most narrow part of the artery which is where the artery pierces the dura covering the optic nerve.