Pharmacokinetics and Differential Regulation of Cytochrome P450 Enzymes in Type 1 Allergic Mice.
Type 1 allergic diseases are characterized by elevated production of specific immunoglobulin E (IgE) for each antigen and have become a significant health problem worldwide. This study investigated the effect of IgE-mediated allergy on drug pharmacokinetics. To further understand differential suppression of hepatic cytochrome P450 (P450) activity, we examined the inhibitory effect of nitric oxide (NO), a marker of allergic conditions. Seven days after primary sensitization (PS7) or secondary sensitization (SS7), hepatic CYP1A2, CYP2C, CYP2E1, and CYP3A activities were decreased to 45%-75% of the corresponding control; however, CYP2D activity was not downregulated. PS7 and SS7 did not change the expression levels of five P450 proteins. Disappearance of CYP1A2 and CYP2D substrates from the plasma was not significantly different between allergic mice and control mice. In contrast, the area under the curve of a CYP1A2-mediated metabolite in PS7 and SS7 mice was reduced by 50% of control values. Total clearances of a CYP2E1 substrate in PS7 and SS7 mice were significantly decreased to 70% and 50% respectively, of the control without altering plasma protein binding. Hepatic amounts of CYP1A2 and CYP2E1 substrates were enhanced by allergic induction, being responsible for each downregulated activity. NO scavenger treatment completely improved the downregulated P450 activities. Therefore, our data suggest that the onset of IgE-mediated allergy alters the pharmacokinetics of major P450-metabolic capacity-limited drugs except for CYP2D drugs. NO is highly expected to participate in regulatory mechanisms of the four P450 isoforms.
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Tadatoshi
T
Tanino
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Akira
A
Komada
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Koji
K
Ueda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Toru
T
Bando
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Yukie
Y
Nojiri
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Yukari
Y
Ueda
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan esakurai@ph.bunri-u.ac.jp.
Eiichi
E
Sakurai
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006967:Hypersensitivity / Q000378:metabolism*; D007073:Immunoglobulin E / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000378:metabolism
D009569:Nitric Oxide; D007073:Immunoglobulin E; D003577:Cytochrome P-450 Enzyme System