Plasma methionine depletion and pharmacokinetic properties in mice of methionine γ-lyase from Citrobacter freundii, Clostridium tetani and Clostridium sporogenes.
PK studies were carried out after a single i.v. administration of 500 and 1000 U/kg by measuring of MGL activity in plasma samples. L-methionine concentration was measured by mass spectrometry. After single i.v. injection of 500U/kg the circulating T1/2of enzymes in mice varies from 73 to 123min. The AUC0-tinfvalues determined for MGL 500U/kg from C. freundii, C. tetani and C. sporogenes are 8.21±0.28, 9.04±0.33 and 13.88±0.39U/(ml×h), respectively. Comparison of PK parameters of three MGL sources in the dose of 500U/kg indicated the MGL C. sporogenes to have better PK parameters: clearance 0.83(95%CI: 0.779-0.871) - was lower than C. tetanii 1.27(95%CI: 1.18-1.36) and C. freundii 1.39(95%CI: 1.30-1.49). Mice plasma methionine decreased to undetectable level 10min after MGL 1000 U/kg injection. After MGL C. sporogenes 500U/kg injection plasma methionine level completely omitted after 10min till 6h, assuming the sustainability of negligible levels of methionine (<5μM) in plasma of mice for about 6h. The recovery of methionine concentration showed the advantageous efficiency of MGL from C. sporogenes: 95% 0.010-0.022 vs 0.023-0.061 for MGL C. freundii and 0.036-0.056 for MGL C. tetani. There are no significant differences between methionine cleavage after MGL C. tetani and MGL C. sporogenes i.v. injection at all doses. MGL from C. sporogenes may be considered as promising enzyme for further investigation as potential anticancer agent.
V.A. Engelgardt Institute of Molecular Biology, Moscow, Russia.
E A
EA
Morozova
V.A. Engelgardt Institute of Molecular Biology, Moscow, Russia.
N V
NV
Anufrieva
N.N. Blokhin Cancer Research Center, Moscow, Russia.
D Zh
DZ
Davydov
Samara University, Samara, Russia; Samara State Medical University, Samara, Russia.
M V
MV
Komarova
I.I. Mechnikov Institute of Vaccine and Sera, Moscow, Russia.
I N
IN
Dyakov
V.A. Engelgardt Institute of Molecular Biology, Moscow, Russia.
A N
AN
Rodionov
V.A. Engelgardt Institute of Molecular Biology, Moscow, Russia. Electronic address: tvd@eimb.ru.
T V
TV
Demidkina
N.N. Blokhin Cancer Research Center, Moscow, Russia; People's Friendship University, Moscow, Russia; V.N. Orekhovich Institute of Biomedical Chemistry, Moscow, Russia. Electronic address: vadimpokrovsky@gmail.com.
V S
VS
Pokrovsky
D000818:Animals; D013437:Carbon-Sulfur Lyases / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016971:Citrobacter freundii / Q000201:enzymology*; D003013:Clostridium / Q000201:enzymology*; D005260:Female; D008715:Methionine / Q000097:blood* / Q000493:pharmacokinetics*; D008810:Mice, Inbred C57BL; D017711:Nonlinear Dynamics; D012044:Regression Analysis
D008715:Methionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase
Methionine depletion; Methionine γ-lyase; Pharmacokinetics