It is well established that the variable binding-site architecture and composition of the P450 metabolizing heme proteins are major modulators of substrate and product specificity. Even the three closely related human liver isozymes, CYP2C9, CYP2C18, and CYP2C19, do not share all substrates and do n
Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs
β Scribed by Theresa S. Klose; Joyce A. Blaisdell; Joyce A. Goldstein
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 106 KB
- Volume
- 13
- Category
- Article
- ISSN
- 1095-6670
No coin nor oath required. For personal study only.
β¦ Synopsis
Extrahepatic tissue distribution of the m-RNAs for the four human CYP2Cs (2C8, 2C9, 2C18, and 2C19) was examined in kidney, testes, adrenal gland, prostate, brain, uterus, mammary gland, ovary, lung, and duodenum. CYP2C mRNAs were detected by RT-PCR using specific primers for each individual CYP2C. CYP2C8 mRNA was detected in the kidney, adrenal gland, brain, uterus, mammary gland, ovary, and duodenum. CYP2C9 mRNA was detected in the kidney, testes, adrenal gland, prostate, ovary, and duodenum. CYP2C18 mRNA was found only in the brain, uterus, mammary gland, kidney, and duodenum and CYP2C19 mRNA was found only in the duodenum. Immunoblot analysis of small intestinal microsomes detected both 2C9 and 2C19 proteins. In addition, genomic clones for CYP2C8 were sequenced, and long-distance PCR was performed to determine the complete gene structure. CYP2C8 spanned a 31 kb region. Comparative analysis of the 2.4 kb upstream region of CYP2C8 with CYP2C9 revealed two previously unidentified transcription factors sites, C/EBP and HPF-1, and the latter might be involved in hepatic expression. Although CYP2C8 has been shown to be phenobarbital inducible, neither a barbiturate-responsive regulatory sequence (a Barbie box) nor a phenobarbital-responsive enhancer module (PBREM) was found within the upstream region analyzed.
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Polymorphisms of CYP450 metabolizer enzymes and transport proteins play crucial roles in the interβindividual variability of drug efficiency. The aim of our study was to predict the frequency of functional variants of __CYP2D6__, __CYP2C19__ and __ABCB1__ genes in the Hungarian population. One hundr
The CYP2C subfamily of human liver P450 isozymes is of major importance in drug metabolism. The most abundant 2C isozyme, CYP2C9, regioselectively hydroxylates a wide variety of substrates. A major obstacle to understanding this specificity in human CYP2C9 is the absence of a 3D structure. A 3D mode