In vitro effects of various heterocyclic thiol compounds and beta-lactam antibiotics on vitamin K-dependent gamma-glutamylcarboxylation activity in liver microsomes.
The in vitro effect of N-methyltetrazolethiol (NMTT), one of the common substituents at the 3'-position of the cephem in various beta-lactam antibiotics, on liver microsomal gamma-glutamylcarboxylation (gamma-carboxylation) activity was examined using solubilized rat liver enzyme. The enzyme activity was inhibited by coexisting with NMTT and NADH, and this inhibitory activity could be suppressed by the addition of a sulfhydryl compound such as dithiothreitol (DTT), glutathione or cysteine. Various five-membered heterocyclic thiol compounds exhibited concentration-dependent inhibition of microsomal gamma-carboxylation activity. These inhibitory actions diminished markedly in the presence of 1 mM DTT. In vitro gamma-carboxylation activity also decreases upon addition of various beta-lactam antibiotics at 1 or 10 mM, depending upon the concentration of the drug. Among the heterocyclic thiol compounds, there is a correlation between their inhibitory activities and hydrophobicities. Thus, the in vitro inhibitory activity of heterocyclic thiol compounds and beta-lactam antibiotics on microsomal gamma-carboxylation activity is not correlated with their molecular structures, but rather depends on their hydrophobicities and with the concentrations in the reaction mixture.
Oka
T
T
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Touchi
A
A
Ezumi
K
K
Yamakawa
M
M
Matsubara
T
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019735:Carbon-Carbon Ligases; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D066298:In Vitro Techniques; D008025:Ligases / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D014812:Vitamin K / Q000378:metabolism*; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D006571:Heterocyclic Compounds; D013438:Sulfhydryl Compounds; D013439:Sulfhydryl Reagents; D047090:beta-Lactams; D014812:Vitamin K; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase