The elevation of cerebral histamine-N-and catechol-O-methyl transferase activities by L-methionine-dl-sulfoximine.

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 S 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 uitro addition of MSO or L-methionine over a wide rangc of histamine and S-adenosyl-Lmethionine concentrations. Rat brain COMT was equally unaffected by MSO and L-methionine. The in uitro 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 involvbnent of aberrant methylation processes in the MSO-induccd seizure. THE ADMINISTRATION of the convulsant, L-methioninedl-sulfoximine, to rats results in a marked and regionally specific decrease of the brain levels of Sadenosyl methionine (SAM) (SCHATZ et al., 1973; SCHATZ & SELLINGER, 1975). It has been known for some time that the joint administration of MSO and L-methionine prevents MSO-induced seizures (LODIN & KOLOUSEK, 1958; SELLINGER et al., 1968), and, more recently, we demonstrated that the MSO-induced depletion of cerebral SAM is also preventcd under these conditions (SCHATZ & SELLINGER, 1975). Two possible mechanisms which may account for the observed depletion of the SAM levels in brain after MSO are (a) an inhibition of the synthesis of SAM via an effect of MSO on ATP: L-methionine-S-adenosyl transferase (E.C. 2.5.1.6) and (b) a stimulation of the utilization of SAM by one or by several members of the large family of cerebral methyl transferase enzymes. Studies from our laboratory (SCHATZ et al., 1973) have indicated that MSO fails to affect the synthesis of SAM either in vivo or in vitro, a finding which agrees with the observations of L~MBARDINI et al. (1970), who noted that MSO serves neither as a substrate nor as an inhibitor of the hepatic ATP: L-methionine-S-adenosyl transferase. In line with the Supported by grants from the United States Public Health Service MH 07417, NS 06294 and a grant from the Epilepsy Foundation of America. Abbreviations used: MSO: L-Methionine-dl-sulfoximine. HMT: histamine-N-methyl transferase. COMT: catechol0-methyl transferase. SAM: S-adenosyl-L-methionine. SAH: S-adenosyl-L-homocysteine. second of the above alternatives, DE RORFRTIS et a/. (1967) described an increase of the cerebral catechol0-methyl transferase activity (E.C. 2.1.1.6) (COMT) after MSO, a n observation which we undertook to explore in more detail, together with a n examination of the effect of MSO on another methyl transferase enzyme of brain tissue, namely histamine-N-methyl transferase (E.C. 2.1.1.8) (HMT). The present report describes findings which lend support to the premise of an effect of MSO on the utilization of SAM, as evidenced by the selective elevation of HMT in mouse and rat brain after MSO, and, more specifically, in 5 out of 7 rat brain neuroanatomical regions. In addition, our results confirm and extend the original observation (DE ROBERTIS et a/., 1967) that MSO affects COMT in vivo and they also show that neither methyl transferase-stimulating effect of MSO is reversed when L-methionine is administered jointly with MSO. A preliminary report has appeared (SCHATZ et al., 1974a). MATERIAL AND METHODS