| [Background and Objective] Cytochrome P450 2C19(CYP2C19) is a clinically important metabolic enzyme responsible for the metabolism of a number o therapeutic drugs and other xenobiotics, such as S-mephenytoin, opeprazole diazepam, proguanil, propranolol and certain antidepressants, it exists genetic polymorphisms. CYP2C19 is the main cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of theii ablity to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers(EMs) or poor metabolisers(PMs). In health} individuals, CYP2C19 genotype normally predicts CYP2C19 phenotype. Fiftten variant alleles(CYP2C19*2 to CYP2C19*15) that predict PMs have been identified. It has been shown that changes in metabolic activity of CYP2C19 may occur due to dietary factors, environmental factors, drug interactions and disease status. The distributin of EM and PM phenotypes shows wide interethnic differences. The incidences of PMs is much higher in Oriental populations (18%~23%) than inCaucasian populations (3%~5%).CYP2C19 EMs and PMs can both influence cancer susceptibility,PMs can rapidly metabolise precarcinogen to carcinogen, and then damage DNA to intermediate cancer occurring , EMs can't detoxify external carcinogen effectively and cause cancer. M.L Williams et al investigates the relationship between CYP2C19 genotype and phenotype in 16 patients with advanced cancer, found that decrease in CYP2C19 enzyme activity could have an impact on the efficacy and toxicity of chemotherapeutic agents and other drugs,used in standard oncology practice. The development of genotype/phenotype discordances should reflect general changes in metabolic capabilities, and also suggest that the genotype/phenotype probes can be used to optimize the clinical treatment of patients with advanced disease states.The tissue locations of CYP2C mRNA have been investigated and reported. Zeldin et al have detected CYP2C8 and CYP2C9 mRNA in kidney. Hukkanen et al detected CYP2C mRNA transcripts in bronchoalveolar macrophages using universal CYP2C primers in RT-PCR analysis. Nakajima et al. reported CYP2C8 protein expressed in lung microsomes, and Mace et al. detected both CYP2C8 and CYP2C18 mRNA transcripts in both bronchial mucosa and peripheral lung tissues. CYP2C8 and CYP1A1 mRNA were found to be the most frequently expressed in adult brain by McFadyen et al. Huang et al. detected CYP2C mRNA in breast tissue, but no individual forms were identified. Zaphiropoulos found CYP2C18 mRNA to be abundantly expressed in the adult epidermis. Several investigators have detected CYP2C mRNA in placenta during different phases, no CYP2C mRNA was detected in full term placenta, and CYP2C mRNA was identified in the first trimester placenta.CYP2C19 is a protein of 490 amino acids encodes by the CYP2C19 gene, which has 9 exons (GenBank accession numbers: L31506,131507, L32982 and L32983) and is mapped to chromosome 10q24.CYP2C19 is synthesized by liver cell and introduce metabolic activity, and it is rarely observed in extrahepatic tissues. T.S.Klose et al examined the distribution of four CYP2Cs (2C8, 2C9, 2C18, 2C19) in extrahepatic tissues including kidney, tests, adrenal gland, prostate, brain, uterus, mammary gland, ovary, lung, and duodenum, and CYP2C19 mRNA was only found in the duodenum.We use the semi-quantitative reverse transcription-polymerase chain reaction method to detect the expression difference of CYP2C19 mRNA between normal and tumor Tissues in ten tissues including liver, and to examine the CYP2C19 protein using western blotting to investigate CYP2C19 mRNA distribution in Chinese han population, and its relationship with tumor.[Methods] 1. Differential expression of CYP2C19 mRNA in cancer and adjacent tissues: CYP2C19 mRNA expression level was detected in cancer tissues and its adjacent normal tissues, including hepatocarcinoma, colorectal cancer, gastric cancer, breast cancer, esophagus cancer, lung cancer, uterus cancer, encephal... |
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