Pharmacokinetics and Metabolism of Apigenin in Female and Male Rats After a Single Oral Administration

Gradolatto, Angéline; Basly, Jean Philippe; Berges, Raymond; Teyssier, Caroline; Chagnon, Marie‐Christine; Siess, Marie Hélène; Canivenc-Lavier, Marie Chantal

doi:10.1124/dmd.104.000893

Cited by 148 publications

(115 citation statements)

References 30 publications

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“…We saw significant decreases in IL-6 secretion with concentrations as low as 1 μM. These data suggest that a plasma concentrations of ∼1.5 μM apigenin, which is achievable through dietary sources (Gradolatto et al 2005), can be an effective suppressor of the SASP.…”

Section: Discussionmentioning

confidence: 65%

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

et al. 2017

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Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cellsstressed cells that accumulate with age in mammalsdisplay a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelialmesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.

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Section: Discussionmentioning

confidence: 65%

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

et al. 2017

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“…A recent study on rats after a single p.o. dose of apigenin has shown a high-elimination half time (f90 hours), suggesting that frequent consumption may result in accumulation of flavonoids in plasma and tissues (42). Studies have further shown that upon absorption, the flavonoids are metabolized by methylation or by conjugation with gluconate or sulfate via dual recycling involving both enteric and enterohepatic pathways (43,44).…”

Section: Discussionmentioning

confidence: 99%

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Shukla

Gupta

2006

Molecular Cancer Therapeutics

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Apigenin (4V ,5,7-trihydroxyflavone) is a promising chemopreventive agent abundantly present in fruits and vegetables that has been shown to promote cell cycle arrest and apoptosis in various malignant cell lines. To determine whether pharmacologic intervention with apigenin has a direct growth inhibitory effect on human prostate tumors implanted in athymic nude mice, we examined cell cycle regulatory molecules as precise molecular targets of apigenin action. Apigenin feeding by gavage to these mice at doses of 20 and 50 Mg/mouse/d in 0.2 mL of a vehicle containing 0.5% methyl cellulose and 0.025% Tween 20 resulted in significant decreases in tumor volume and mass of androgen-sensitive 22Rv1 and androgen-insensitive PC-3-implanted cells. Oral intake of apigenin resulted in dose-dependent (a) increase in the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18; (b) down-modulation of the protein expression of cyclins D1, D2, and E; and cyclin-dependent kinases (cdk), cdk2, cdk4, and cdk6; (c) decrease in retinoblastoma phosphorylation at serine 780; (d) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27; and (e) decrease in the binding of cyclin E toward cdk2 in both types of tumors. In addition, apigenin feeding resulted in stabilization of p53 by phosphorylation at serine 15 in 22Rv1 tumors, which seems to exhibit p53-dependent growth inhibitory responses. Apigenin intake by these mice also resulted in induction of apoptosis, which positively correlated with serum and tumor apigenin levels. Taken together, this is the first systematic in vivo study showing the involvement of cell cycle regulatory proteins as potential molecular targets of apigenin. [Mol Cancer Ther 2006;5(4):843 -52]

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“…The relative amounts of parent compound and metabolites were higher in female serum than those in males. Gender-related differences in drug metabolism, especially in the rat, have been reported for numerous drugs and occur in both phase I and phase II metabolism (Gradolatto et al, 2005;Anari et al, 2006;Prakash et al, 2007aPrakash et al, ,b, 2008. One factor commonly known to contribute to gender-and species-dependent metabolism is differential expression of drug metabolism enzymes, especially cytochrome P450 isoforms (Martignoni et al, 2006;Richert et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Excretion, Metabolism, and Pharmacokinetics of CP-945,598, a Selective Cannabinoid Receptor Antagonist, in Rats, Mice, and Dogs

Miao

Scott²,

Griffith³

et al. 2011

Drug Metab Dispos

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ABSTRACT:1-(8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4-(ethylamino)piperidine-4-carboxamide (CP-945,598) is an orally active antagonist of the cannabinoid CB-1 receptor that progressed into phase 3 human clinical trials for the treatment of obesity. In this study, we investigated the metabolic fate and disposition of CP-945,598 in rats, Tg-RasH2 mice, and dogs after oral administration of a single dose of [ 14 C]CP-945,598. Total mean recoveries of the radioactive dose were 97.7, 97.8, and 99.3% from mice, rats, and dogs, respectively. The major route of excretion in all three species was via the feces, but on the basis of separate studies in bile duct-cannulated rats and dogs, this probably reflects excretion in bile rather than incomplete absorption. CP-945,598 underwent extensive metabolism in all three species, because no unchanged parent compound was detected in the urine across species. The primary metabolic pathway of CP-945,598 involved N-deethylation to form an N-desethyl metabolite (M1). M1 was subsequently metabolized by amide hydrolysis, oxidation, and ribose conjugation to numerous novel and unusual metabolites. The major circulating and excretory metabolites were species-dependent; however, several common metabolites were observed in more than one species. In addition to parent compound, M1, M3, M4, and M5 in rats, M1, M3, and M4 in mice, and M1 and M2 in dogs were identified as the major circulating metabolites. Gender-related differences were also apparent in the quantitative and qualitative nature of the metabolites in rats. An unprecedented metabolite, M4, formed by deamidation of M1 or M3 (N-hydroxy-M1), but not by decarboxylation of M2, was identified in all species. M4 was nonenzymatically converted to M5.

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Pharmacokinetics and Metabolism of Apigenin in Female and Male Rats After a Single Oral Administration

Cited by 148 publications

References 30 publications

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Excretion, Metabolism, and Pharmacokinetics of CP-945,598, a Selective Cannabinoid Receptor Antagonist, in Rats, Mice, and Dogs

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