DIMETHYLTHIOUREA, A HYDROXYL RADICAL SCAVENGER, IMPEDES THE INACTIVATION OF METHIONINE SYNTHASE BY NITROUS OXIDE IN MICE

Dimethylthiourea (DMTU), a potent scavenger of hydroxyl radicals,was studied to see if it attenuated the inactivation of methioninesynthase produced by nitrous oxide in mice. Mice were giveni.p. injections of DMTU 0.5–4.0 mg g^–1 or salineand, 1 h after injection, were exposed to 66% nitrous oxidein oxygen for periods of 0.5–8 h. At given times afternitrous oxide exposure, higher methionine synthase activitieswere found in the livers, kidneys and brains of mice injectedwith DMTU than in the salineinjected animals. These higher methioninesynthase activities in the DMTU-treated animals representeda delay in the enzyme inactivation produced by nitrous oxide,as the difference in activities between the DMTU-injected andsaline-injected mice decreased with increasing duration of exposureto nitrous oxide. Greater differences in methionine synthaseactivities between the DMTU- and saline-injected animals wereobserved with increasing doses of DMTU. The rate of enzyme inactivationfollowing exposure to nitrous oxide was greater in liver andleast in brain, and the difference in activities between thetwo groups varied with the organ examined. DMTU exhibited itsgreatest effect in the kidney, where methionine synthase activitieswere nearly doubled in the DMTU 2.0 mg g^–1 injected comparedwith the saline-injected mice after 1-h exposure to 66% nitrousoxide. Following a marked inactivation of methionine synthaseby exposing mice to 66% nitrous oxide for 4 h, injection ofDMTU 2.0 mg g^–1 at the end of exposure to nitrous oxidedid not enhance, but impaired, the recovery of enzyme activity.The findings are consistent with the hypothesis that nitrousoxide combines with the vitamin B₁₂ molecule of methionine synthaseto form hydroxyl radical that reacts with and inactivates theenzyme, and that DMTU slows this inactivation by scavenginghydroxyl radicals A preliminary report of these results was published in Anesthesiology1988; 69: A434Address for correspondence: Anesthesiology Service (129), VeteransAdministration Medical Center, 4150 Clement Street, San Francisco,CA 94121, U.S.A.