THE ELEVATION OF CEREBRAL HISTAMINE‐N‐AND CATECHOL‐O‐METHYL TRANSFERASE ACTIVITIES BY l‐METHIONINE‐dl‐ SULFOXIMINE¹

Abstract

Abstract— The administration of the convulsant, l‐methionine‐dl‐sulfoximine (MSO), increased histamine N‐methyl transferase (E.C. 2.1.1.8) (HMT) activity in rat and mouse brain and, to a lesser extent, catechol‐O‐methyl transferase (E.C. 2.1.1.6) (COMT) activity in rat brain. The duration of this effect was shortened by co‐administration of l‐methionine. The increased HMT activity was seen in 5 or 7 rat brain regions tested. l‐Methionine administration had no effect on the activity of either enzyme. Partially purified HMT preparations from rat or guinea‐pig brain exhibited no alterations in activity after the in vitro addition of MSO or l‐methionine over a wide range of histamine and S‐adenosyl‐l‐methionine concentrations. Rat brain COMT was equally unaffected by MSO and l‐methionine. The in vitro inhibition of HMT and COMT by S‐adenosyl‐l‐homocysteine was the same whether tested on preparations derived from MSO‐treated or control animals. The data are discussed with respect to the possible involvement of aberrant methylation processes in the MSO‐induced seizure.

S-Adenosyl-l-homocysteine in brain

“…We have also investigated the validity of using the AdoMet/AdoHcy ratio as an index of transmethylation activity of brain tissue, as has been previously suggested (2,7).…”

“…Attempts to elucidate the mechanism(s) responsible for the seizureproducing properties of methionine sulfoximine (MSO) have demonstrated that this agent alters methylation processes in brain. Administration of MSO resulted in (a) decreased levels of cerebral S-adenosylmethionine (AdoMet) in the rat (1), (b) increased activity of histamine-Nmethyltransferase (HMT) in rat and mouse brain (2), and (c) increased activity of catechol-O-methyltransferase (COMT) in rat brain (2,3). The lack of effect of MSO (in vivo or in vitro) on the activity of the enzyme responsible for AdoMet synthesis (ATP:L-methionine-S-adenosyltransferase) (4,5), paired with the finding of the elevated cerebral HMT and COMT activity (in vivo) (2), has led to the suggestion that MSO acts by increasing the flux through methylation pathways (2).…”

“…Administration of MSO resulted in (a) decreased levels of cerebral S-adenosylmethionine (AdoMet) in the rat (1), (b) increased activity of histamine-Nmethyltransferase (HMT) in rat and mouse brain (2), and (c) increased activity of catechol-O-methyltransferase (COMT) in rat brain (2,3). The lack of effect of MSO (in vivo or in vitro) on the activity of the enzyme responsible for AdoMet synthesis (ATP:L-methionine-S-adenosyltransferase) (4,5), paired with the finding of the elevated cerebral HMT and COMT activity (in vivo) (2), has led to the suggestion that MSO acts by increasing the flux through methylation pathways (2). The product of these methylations, S-adenosylhomocysteine (AdoHcy), has been proposed as a regulator of the activities of HMT (6,7), COMT (8), indolethylamine-N-methyltransferase (9), tRNA methyltransferases (10,11), and phenylethanolamine-N-methyltransferase (12).…”

“…3.3.1.1.). The effect of methionine on the above parameters was also studied since methionine antagonizes MSO seizures (13,14) as well as the biochemical alterations in AdoMet (1), HMT, and COMT (2). AdoHcy levels after the administration of dihydroxyphenylalanine (DOPA) and cycloleucine were also determined since both agents decrease brain AdoMet , the former by increasing the utilization of methyl groups (15,16), and the latter by inhibiting AdoMet synthesis (16,17).…”

Effect of Methionine Sulfoximine (MSO) on the Regional Activity of Choline Acetyltransferase in Rat Brain

“…Following the discovery of MSO, there have been several studies to identify its mechanism(s) of action in animals. It has been shown to cause anatomical changes (4,5,9,16,19) in the brain structure of laboratory animals and in order to further clarify the effect of MSO on the brain its action on several brain neurochemical parameters has been studied, including glycogen and related enzymes (2,6,7,16), amino acid metabolism (8,15,26,27), ammonia (7), brain amines and their enzymes (5,21,25) as well as other enzyme systems in mammalian brain (5,10,11,20,23,24). It has also been demonstrated that the amino acid, methionine, can antagonize the uptake and binding of MSO in certain brain areas (22) as well as some of its effects (12,18).…”