Discovery of the RNA Synthetic Activity of Glutamate Dehydrogenase andIts Application in Drug Metabolism Research

Glutamate dehydrogenase (GHD) synthesizes some RNAs that regulate mRNA abundance in response to the environment. The connection of gene expression and drug metabolism by the GDH-synthesized RNA has not been dem- onstrated experimentally. The regulation of the mRNAs encoding the drug-metabolizing enzymes was studied by northern hybridization using the GDH-synthesized RNAs as probes. The mRNAs encoding cytochrome P-450 reductase, UDP- glucosyltransferase, alternative oxidase, and ABC-transporters were upregulated by the administered ATP+UTP+GTP. Also superoxide dismutase and GSH S-transferase were upregulated by administered ATP. The untreated control, GTP, and UTP did not upregulate any of the mRNAs. The mRNAs encoding the enzymes were coordinately regulated at the molecular level. All the enzymes are also active in drug detoxication in mammals. Photometric assays of enzyme activi- ties confirmed that the enzymes were present at levels proportional to their respective encoding mRNAs as detected by the GDH-synthesized RNA probes. Genetic code-based nucleic acid probes were partially accurate in detecting the mRNAs encoding the enzymes. Therefore, GDH-synthesized RNAs are important genetic metabolic probes for the screening of mRNAs encoding the drug metabolizing enzymes. Nucleoside triphosphates and analogs are antihypertensives, antineo- plastics, antiarrhythmics, antimetabolites, antiviral agents etc and they induce GDH isomerization.