Contribution of enzymic alpha, gamma-elimination reaction in detoxification pathway of selenomethionine in mouse liver.
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.
Okuno
T
T
Division of Environmental Health, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. okuno@pharm.setsunan.ac.jp
Kubota
T
T
Kuroda
T
T
Ueno
H
H
Nakamuro
K
K
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*
D002087:Butyrates; C005087:alpha-ketobutyric acid; D000641:Ammonia; D012645:Selenomethionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase