title: Contribution of enzymic alpha, gamma-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 H(2)Se, which is consequently methylated to CH(3)SeH, (CH(3))(2)Se, and (CH(3))(3)Se(+). In this study, we estimated that the median lethal single oral dose (LD(50)) was 67.0 mg/kg. We also found that (CH(3))(3)Se(+) was quickly produced in mouse liver after single oral administration of SeMet. This result suggested the existence of a quick alpha,gamma-elimination pathway. We measured the amounts of alpha-ketobutyrate, NH(3), and CH(3)SeH produced by enzymic alpha,gamma-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 alpha,gamma-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 gamma-lyase (EC 4.4.1.11) contributing to the alpha,gamma-elimination reaction of SeMet and cystathionine gamma-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 alpha-ketobutyrate was much the same as that from nontreated mouse liver. However, the amount of alpha-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 from CH(3)SeH increased gradually. This phenomenon was not observed in the PPG-pretreated group. Furthermore, the protein fraction that had the alpha,gamma-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 CH(3)SeH by an alpha,gamma-elimination enzyme analogous to bacterial L-methionine gamma-lyase, in addition to the generally acceptable pathway via SeCyH.
authors.affiliation: Division of Environmental Health, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. okuno@pharm.setsunan.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Okuno
authors.forename: T
authors.initials: T
authors.lastname: Kubota
authors.forename: T
authors.initials: T
authors.lastname: Kuroda
authors.forename: H
authors.initials: H
authors.lastname: Ueno
authors.forename: K
authors.initials: K
authors.lastname: Nakamuro
mesh_terms: D000641:Ammonia / Q000032:analysis / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000032:analysis / Q000378:metabolism; D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D008658:Inactivation, Metabolic; D007928:Lethal Dose 50; D008099:Liver / Q000201:enzymology*; D008297:Male; D008745:Methylation; D051379:Mice; D008813:Mice, Inbred ICR; D012645:Selenomethionine / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D002087:Butyrates; C005087:alpha-ketobutyric acid; D000641:Ammonia; D012645:Selenomethionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase