Pharmacokinetics and Differential Regulation of Cytochrome P450 Enzymes in Type 1 Allergic Mice

Abstract

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.

Hepatic Flavin-Containing Monooxygenase 3 Enzyme Suppressed by Type 1 Allergy-Produced Nitric Oxide

“…Concerning the contribution of T helper 2 cell-activated immune systems, little information is available on the ability of cytokines to directly regulate FMO1 and FMO3 expression. We reported that CYP1A2, CYP2C, CYP2E1, and CYP3A activities were markedly suppressed by allergy-induced NO production-but not the cytokine-dependent pathway-resulting in marked changes in drug pharmacokinetics (Tanino et al, 2016). Our results differed from the significant contribution of T helper 1 cellactivated proinflammatory cytokines (cytokine-dependent pathway) in lipopolysaccharide-stimulating inflammatory diseases (Renton 2001(Renton , 2004Morgan et al, 2008).…”

“…Patients with bronchial asthma and allergic rhinitis show an increased level of nitric oxide (NO) in exhaled air (Alving et al, 1993;Kharitonov et al, 1997). We also found that type 1 allergy with high serum IgE concentrations enhance serum NO concentrations (Tanino et al, 2016). Park et al (1999) suggested that excessive activation of the https://doi.org/10.1124/dmd.117.076570.…”

“…The liver was excised and washed three times with ice-cold 50 mM Tris-HCl (pH 7.4). Further treatments for high-performance liquid chromatography (HPLC) assay were detailed in our recent study (Tanino et al, 2016). All animal experiments were approved by the Tokushima Bunri University Faculty of Pharmaceutical Sciences' Committee for the care and use of laboratory animals.…”

“…were determined using a Nitrate/Nitrite Colorimetric Assay Kit (Cayman Chemical, Ann Arbor, MI) according to the manufacturer's instructions. The assay conditions were detailed in our recent report (Tanino et al, 2016). Enzyme Assay.…”

“…Enzyme Assay. Liver microsomes from control and treated mice were prepared as described previously (Tanino et al, 2016). Protein concentrations were determined with a BCA Protein Assay Kit (Thermo Fisher Scientific Inc., Rockford, IL) and bovine serum albumin as a protein standard.…”