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Toxicology and pharmacology of rho‐iso‐alpha acids (RIAA), hop‐derived inhibitors of prostaglandin E2 formation
Author(s) -
Shenai Bhaskar R.,
Darland Gary,
Lerman Robert,
Tripp Matthew,
Bland Jeffrey S.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1145
Subject(s) - alpha (finance) , hop (telecommunications) , pharmacology , prostaglandin e2 , chemistry , biology , medicine , genetics , computer science , telecommunications , surgery , construct validity , patient satisfaction
Rho‐iso‐alpha acids (RIAA)—derived from hops ( Humulus lupulus ) strobiles by supercritical CO 2 extraction and sodium borohydride reduction—is used as a flavoring agent in the beer industry. Recently, it was demonstrated that RIAA inhibits the formation of prostaglandin E 2 (PGE 2 ) in lipopolysaccharide (LPS)‐activated mouse macrophage RAW264.7 cells. In a prelude to the development of RIAA as an anti‐inflammatory agent, a 21‐day study to assess the oral toxicity of RIAA was conducted in CD‐1 mice. A total of 40 mice were orally administered RIAA by gavage at doses of 25, 75, and 250 mg/kg/day. The mice were evaluated for changes in clinical signs, food consumption, body weight and other parameters. Overall, it was observed that RIAA was well tolerated for 21 days, with the only notable treatment effects occurring in the liver (minimal centrilobular hepatocellular hypertrophy) and spleen (increased incidence and/or severity of extramedullary hematopoesis) at the highest dosage. Further, the effect of RIAA on the major human cytochrome (CYP) P450s involved in drug metabolism was investigated using recombinant singly expressed enzymes. RIAA displayed only weak interactions (IC 50 s > 10 μM) with CYP1A2, CYP2D6, CYP2E1 and CYP3A4, and moderate inhibition of CYP2C19 (IC 50 6.13 μM). Significant inhibition was only observed for CYP2C9 (IC 50 0.20 μM). These data suggest that RIAA is unlikely to alter the metabolic clearance of drugs that are primarily metabolized by these CYP isozymes, with the possible exception of CYP2C9. This study was supported by Metagenics, Inc.