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Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs

T S Klose1, J A Blaisdell, J A Goldstein

  • 1Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Journal of Biochemical and Molecular Toxicology
|September 16, 1999
PubMed

Insights

This study maps the tissue distribution of human CYP2C mRNAs, finding varied expression patterns across organs. It also details the gene structure of CYP2C8 and identifies novel regulatory elements.

Area of Science:

  • Pharmacogenomics
  • Molecular Biology
  • Biochemistry

Background:

  • The cytochrome P450 family, specifically CYP2Cs, plays a crucial role in drug metabolism.
  • Understanding the extrahepatic tissue distribution of CYP2C isoforms is essential for predicting drug interactions and toxicity beyond the liver.

Purpose of the Study:

  • To comprehensively map the extrahepatic mRNA distribution of human CYP2C8, CYP2C9, CYP2C18, and CYP2C19.
  • To elucidate the gene structure of CYP2C8 and identify potential regulatory elements influencing its expression.

Main Methods:

  • Reverse transcription-polymerase chain reaction (RT-PCR) was employed to detect CYP2C mRNA in various human tissues.
  • Immunoblot analysis was used to confirm protein expression of CYP2C9 and CYP2C19.
  • Long-distance PCR and genomic sequencing were utilized to determine the gene structure of CYP2C8.

Main Results:

  • CYP2C8 mRNA was detected in kidney, adrenal gland, brain, uterus, mammary gland, ovary, and duodenum.
  • CYP2C9 mRNA was found in kidney, testes, adrenal gland, prostate, ovary, and duodenum.
  • CYP2C18 and CYP2C19 mRNAs exhibited more restricted tissue distribution, with CYP2C19 exclusively detected in the duodenum. Both CYP2C9 and CYP2C19 proteins were identified in small intestinal microsomes. The CYP2C8 gene spans 31 kb, and its upstream region contains novel transcription factor sites (C/EBP and HPF-1).

Conclusions:

  • The distinct extrahepatic tissue distribution of CYP2C isoforms suggests specialized roles in various organs.
  • The identification of novel regulatory elements in the CYP2C8 upstream region provides insights into its transcriptional control.
  • Further research is warranted to explore the functional implications of these findings in drug metabolism and disease.

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