title: Gender Difference of Hepatic and Intestinal CYP3A4 in CYP3AHumanized Mice Generated by a Human Chromosome-engineering Technique.
abstract: Cytochrome P450 3A4 (CYP3A4) is an important drug-metabolizing enzyme that is expressed in the liver and small intestine of humans. Various factors influence the expression of CYP3A4, but gender difference in CYP3A4 expression remains debatable.
  
  
  
  To clarify gender difference of hepatic and intestinal CYP3A4 in CYP3A-humanized mice generated by a human artificial chromosome (HAC) vector system. The CYP3A-humanized (CYP3AHAC) mice have essential regulatory regions, including promoters and enhancers, and unknown elements affecting the expression of CYP3A4.
  
  
  
  We examined the expression and activity of hepatic and intestinal CYP3A4 in male and female CYP3A-HAC mice. CYP3A activity was determined as α- and 4-hydroxylation activity of triazolam in liver and intestinal microsomes. Expression level of CYP3A protein was determined by Western blot analysis. Expression level of CYP3A4 mRNA was measured by quantitative real-time PCR.
  
  
  
  The results showed that triazolam hydroxylation activities and protein levels of CYP3A in the liver were significantly higher in female than in male CYP3A-HAC mice, whereas those in the intestine were not significantly different between the genders. In addition, the expression of CYP3A4 mRNA showed a tendency similar to that found for the activity and expression of CYP3A protein in the liver and intestine of CYP3A-HAC mice.
  
  
  
  These findings suggest that the expression and activity levels of CYP3A4 in the liver are higher in females than in males, whereas there is no gender difference in the levels in the intestine of CYP3A-HAC mice.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Abe
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishi-cho, Yonago, Tottori, Japan.|Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000818:Animals; D022222:Chromosomes, Artificial, Human; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice
chemical_list: D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A-humanized mice.; CYP3A4; humanized mice; intestine; liver; sex