Abstract—The mechanism of histamine methyltransferase (HMT) inhibition byS‐adenosylhomocysteine (SAH) has been investigated on a partially purified enzyme from guinea‐pig brain. The kinetic data indicated that this inhibition was competitive with respect toS‐adenosylmethionine (SAMe) and noncompetitive with respect to histamine. TheKt, values (about 5 ± 10−6M in both cases) indicated that SAH had a higher affinity than SAHe or histamine for the enzyme.In rats, after administration of a small dose of SAH, methylation of intracisternally injected [3H]histamine was not modified.However, treatment withl‐DOPA or pyrogallol induced a decrease in [3H]histamine methylation, presumably due to a modification in the SAMe/SAH ratio in the brain. Hence, histamine methylation in brain could be regulated according to the value of this ratio and thus related to methylation of other bio