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Many studies concerning gamma-glutamyl transpeptidase (GGTP) in hepatocellular carcinoma (HCC) have suggested that changes in hepatic GGTP expression may be closely related to the development of HCC. However, its mechanisms are not well known, and genomic analysis of the specific GGTP to HCC is also lacking. Recently, the human GGTP complementary DNA (cDNA) sequences from fetal liver, placenta, and HepG2 cells have been published. In the present study, we sought to clarify the distribution of the GGTP messenger RNA (mRNA) molecular species in human liver and determine whether alterations in GGTP mRNA expression occur upon the development of HCC. The specific primer sets for reverse-transcription polymerase chain reaction (PCR) corresponding to the 5'-noncoding human GGTP mRNA of fetal liver (type A), HepG2 cells (type B), and placenta (type C) were prepared. Oligonucleotide probes specific for each type of mRNA were also synthesized. Liver tissues were obtained from patients with or without HCC, and total RNA was extracted. Total RNA was also extracted from various organs obtained from one male patient upon autopsy. Types of GGTP mRNAs were analyzed using type-specific primer sets and oligonucleotide probes. The types of GGTP mRNA varied in different organs. In normal liver and diseased liver without HCC, the main type of GGTP mRNA was type A. The expression was monogenic in most cases but was polygenic in some cases. In the polygenic cases, type C was common, but type B was found occasionally. On the other hand, type B was predominant in cancerous tissues with HCC. In noncancerous tissues of livers with HCC, the main types were types A and B. The prevalence of type B was significantly higher in both cancerous and noncancerous tissues of livers with HCC than in livers without HCC. The prevalence of type A in cancerous tissue, but not in noncancerous tissue, was significantly lower than in livers without HCC. These results strongly suggested that the GGTP mRNA expression in human liver may shift from type A to type B during the development of HCC. The high prevalence of type B in noncancerous tissues suggested that the shift of the GGTP mRNA may occur from the preneoplastic stage of hepatocytes.