Contribution of Enzymic α,γ-Elimination Reaction in Detoxification Pathway of Selenomethionine in Mouse Liver

Abstract

The objective of this study was to clarify the detoxification pathways of selenomethionine (SeMet) in mouse liver. It has been postulated that SeMet may be metabolized to selenocysteine (SeCyH) via a pathway similar to methionine (Met). CySeH may be decomposed to H2Se, which is consequently methylated to CH3SeH, (CH3)2Se, and (CH3)3Se+. In this study, we estimated that the median lethal single oral dose (LD50) was 67.0 mg/kg. We also found that (CH3)3Se+ was quickly produced in mouse liver after single oral administration of SeMet. This result suggested the existence of a quick α,γ-elimination pathway. We measured the amounts of α-ketobutyrate, NH3, and CH3SeH produced by enzymic α,γ-elimination reaction of SeMet in the liver of periodate-oxidized adenosine (PAD) or d,l-propargylglycine (PPG)-treated mice in order to verify the existence of α,γ-elimination enzyme. PAD is an inhibitor of S-adenosylhomocysteinase (EC 3.3.1.1), which is necessary for conversion of SeMet to SeCyH. PPG is an effective inhibitor of the pyridoxal 5′-phosphate (PLP)-containing enzyme bacterial l-methionine γ-lyase (EC 4.4.1.11) contributing to the α,γ-elimination reaction of SeMet and cystathionine γ-lyase (EC 4.4.1.1) relating to conversion of SeMet to SeCyH. When SeMet was incubated with the S9 fraction from liver of PAD-treated mice, the formation of α-ketobutyrate was much the same as that from nontreated mouse liver. However, the amount of α-ketobutyrate formed significantly decreased in the reaction of SeMet with S9 fraction from the liver of PPG-treated mice. In an in vivo experiment using mice treated with PAD before a toxic dosage of SeMet, the amount of SeMet in the liver decreased and the amount of acid-volatile Se derived fromCH3SeH increased gradually. This phenomenon was not observed in the PPG-pretreated group. Furthermore, the protein fraction that had the α,γ-elimination enzyme activity was found in mouse liver cytosol by gel chromatographic technique. The results of this study indicated that SeMet was directly metabolized to CH3SeH by an α,γ-elimination enzyme analogous to bacterial l-methionine γ-lyase, in addition to the generally acceptable pathway via SeCyH.