Regulation of Cytochrome P4501A1 Expression in Rat Small Intestine

• Published in: Drug metabolism and disposition Vol. 25; no. 1; pp. 21 - 26
• Main Authors: ZHANG, Q.-Y, WIKOFF, J, DUNBAR, D, FASCO, M, KAMINSKY, L
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-01-1997
• Subjects: Analytical, structural and metabolic biochemistry; Animals; beta-Naphthoflavone - pharmacology; Biological and medical sciences; Cytochrome P-450 CYP1A1 - biosynthesis; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1A2 - biosynthesis; Enzyme Induction; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Immunoblotting; Intestinal Mucosa - enzymology; Intestine, Small - enzymology; Liver - enzymology; Male; Microsomes, Liver - enzymology; Oxidoreductases; Polymerase Chain Reaction; Rats; Rats, Wistar; Receptors, Aryl Hydrocarbon - metabolism; RNA, Messenger - analysis; Vertebrata; Regulation(control); Mammalia; Enzymatic activity; Rat; Isozyme; Animal; Cytochrome P450; Rodentia; In vitro; Small intestine
• ISSN: 0090-9556; 1521-009X

The predominant inducible cytochrome P450 (CYP) in rat small intestine is CYP1A1, which, when induced to elevated levels by
xenobiotics or dietary constituents, has the potential to metabolize and consequently reduce the systemic uptake of low concentrations
of orally ingested, bioactivatable polycyclic aromatic hydrocarbons and heterocyclic aromatic amines. We investigated the
regulation of small intestinal CYP1A1 in an effort to develop its anticancer potential. The time courses of hepatic and intestinal
CYP1A1 induction by β-naphthoflavone (BNF) were compared quantitatively at the protein and mRNA levels by immunoblot and competitive
RNA-polymerase chain reaction analyses. CYP1A1 mRNA levels in both organs increased sharply and were maximal at ∼6 hr and
returned to near basal levels by 12 hr after BNF treatment. In contrast, hepatic CYP1A2 mRNA levels increased much more gradually.
Small intestinal CYP1A2 mRNA concentrations were insufficient to support translation of detectable protein. Maximal levels
of intestinal and hepatic CYP1A1 protein occurred between 12 and 24 hr, and 24 and 48 hr, respectively, after BNF. Intestinal
CYP1A1 protein was detectable earlier and for a shorter duration than hepatic CYP1A1. CYP1A1 induction was first detected
in crypt cells 3 hr before the appearance of activity in villous cells, and maximal levels of activity were reached in crypt
cells 12 to 18 hr before maximal and 1.5-fold (per mg protein) higher responses in villous cells—induction thus occurs in
both villous and crypt cells. Previously detected decreases in CYP1A1 inducibility from duodenum to ileum correlated with
decreases in immunoblot determined-Ah receptor levels. Intestinal CYP1A1 induction does not involve the glucocorticoid receptor
in contrast to hepatic induction. These studies have revealed several novel features of small intestinal CYP1A1 regulation.