Time-dependent Induction of Rat Hepatic CYP1A1 and CYP1A2 Expression after Single-dose Administration of the Anti-angiogenic Agent TSU-68

Kitamura, Reiko; Matsuoka, Kazuaki; Nagayama, Shigeya; Otagiri, Masaki

doi:10.2133/dmpk.23.421

Cited by 11 publications

(5 citation statements)

References 21 publications

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“…A 24-h-treatment period was used in this study, because it was found to be an appropriate length of time to observe protein induction by several inducers [59,[63][64][65]. The increase in CYP1A1 protein levels and enzyme activities reached a maximum at 12-20 h and then remained constant up to 24 h after treatment with a single dose of inducers before slowly dropping to background levels [59,[63][64][65]. In contrast, CYP1A1 mRNA reached its highest level as early as 3-5 h [65][66][67][68][69].…”

Section: The Effect Of 3-aba Pretreatment On Activation Of 3-aba By Rmentioning

confidence: 99%

3-Aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone, induces biotransformation enzymes in rat kidney and lung

Stiborová

Dračínská

Martínková

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

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3-aminobenzanthrone (3-ABA) is the metabolite of the carcinogenic air pollutant 3-nitrobenzanthrone (3-NBA). 3-ABA was investigated for its ability to induce cytochrome P450 1A1 (CYP1A1) and NAD(P)H:quinone oxidoreductase (NQO1) in kidney and lung of rats, and for the influence of such induction on DNA adduct formation by 3-ABA and 3-NBA. NQO1 is the enzyme that reduces 3-NBA to N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) and CYP1A enzymes oxidize 3-ABA to the same intermediate. When activated by cytosolic and and/or microsomal fractions isolated from rat lung, the target organ for 3-NBA carcinogenicity, and kidney, both compounds generated the same DNA-adduct pattern, consisting of five adducts. When pulmonary cytosols isolated from rats that had been treated i.p. with 40 mg/kg bw of 3-ABA were incubated with 3-NBA, DNA adduct formation was up to 1.7-fold higher than in incubations with cytosols from control animals. This increase corresponded to an increase in protein level and enzymatic activity of NQO1. In contrast, no induction of NQO1 expression by 3-ABA treatment was found in the kidney. Incubations of 3-ABA with renal and pulmonary microsomes of 3-ABA-treated rats led to an increase of up to a 4.5-fold in DNA-adduct formation relative to controls. The stimulation of DNA-adduct formation correlated with a higher protein expression and activity of CYP1A1 induced by 3-ABA. These results show that by inducing lung and kidney CYP1A1 and NQO1, 3-ABA increases its own enzymatic activation as well as that of the environmental pollutant, 3-NBA, thereby enhancing the genotoxic and carcinogenic potential of both compounds.

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Section: The Effect Of 3-aba Pretreatment On Activation Of 3-aba By Rmentioning

confidence: 99%

3-Aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone, induces biotransformation enzymes in rat kidney and lung

Stiborová

Dračínská

Martínková

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…Some drugs, such as dasatinib, nicotine, TSU-68, insulin, can induce the expression or activity of CYP1A1 (Kitamura et al. 2008 ; Wang et al. 2009 ; Alsaad 2018 ; Kuzgun et al.…”

Section: Discussionmentioning

confidence: 99%

In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression

Shan¹,

Shi²,

Hu³

et al. 2022

Pharmaceutical Biology

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Context Toddalolactone, the main component of Toddalia asiatica (L.) Lam. (Rutaceae), has anticancer, antihypertension, anti-inflammatory, and antifungal activities. Objective This study investigated the metabolic characteristics of toddalolactone. Materials and methods Toddalolactone metabolic stabilities were investigated by incubating toddalolactone (20 μM) with liver microsomes from humans, rabbits, mice, rats, dogs, minipigs, and monkeys for 0, 30, 60, and 90 min. The CYP isoforms involved in toddalolactone metabolism were characterized based on chemical inhibition studies and screening assays. The effects of toddalolactone (0, 10, and 50 µM) on CYP1A1 and CYP3A5 protein expression were investigated by immunoblotting. After injecting toddalolactone (10 mg/kg), in vivo pharmacokinetic profiles using six Sprague–Dawley rats were investigated by taking 9-time points, including 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h. Results Monkeys showed the greatest metabolic capacity in CYP-mediated and UGT-mediated reaction systems with short half-lives ( T 1/2 ) of 245 and 66 min, respectively, while T 1/2 of humans in two reaction systems were 673 and 83 min, respectively. CYP1A1 and CYP3A5 were the major CYP isoforms involved in toddalolactone biotransformation. Induction of CYP1A1 protein expression by 50 μM toddalolactone was approximately 50% greater than that of the control (0 μM). Peak plasma concentration ( C max ) for toddalolactone was 0.42 μg/mL, and T max occurred at 0.25 h post-dosing. The elimination t 1/2 was 1.05 h, and the AUC 0–t was 0.46 μg/mL/h. Conclusions These findings demonstrated the significant species differences of toddalolactone metabolic profiles, which will promote appropriate species selection in further toddalolactone studies.

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“…When the effect of TSU-68 on both the ORR and adverse events is considered, it can be said that TSU-68 decreases the efficacy of SOX treatment. TSU-68 is thought to induce CYP1A1 and 1A2 [21], while FT, the main compound of S-1, is mainly metabolized by CYP2A6 [22]. Since CYP1A1 and CYP1A2 can metabolize FT, a potential drug interaction between TSU-68 and S-1 may influence the efficacy of the TSU-68+SOX combination.…”

Section: Discussionmentioning

confidence: 99%

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.

Shin

Lee

Chung

et al. 2013

JCO

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492 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin-based treatment (FOLFOX, CapeOX) combined with bevacizumab is one of the standard chemotherapies for metastatic CRC. However, several clinical studies performed using S-1 plus oxaliplatin (SOX) indicate that SOX is a treatment option for metastatic CRC. TSU-68 (orantinib) is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and has promising efficacy and high safety. The recommended phase II dose of TSU-68 plus SOX has been determined in a phase I study. This trial aimed to evaluate the efficacy of TSU-68 in combination with SOX. Methods: We performed an open-label multicenter randomized phase II trial in Korea. Treatment-naive metastatic CRC patients with a performance status 0 or 1 were randomized in a ratio of 1:1 to receive either TSU-68 plus SOX (group A) or SOX (group B). The primary endpoint was progression-free survival (PFS). Results: We randomized 105 patients (52 patients, group A and 53 patients, group B). Median PFS was 7.0 months in group A (hazard ratio [HR], 1.057) and 7.2 months in group B (P = 0.8401). The most frequent grade 3/4 events were thrombocytopenia (9.6% vs 26.4%), neutropenia (13.5% vs 15.1%), and anemia (3.8% vs 13.2%). We observed a difference between the 2 groups in all grades of anemia (15.4% vs 32.1%), diarrhea (30.8% vs 47.2%), vomiting (50.0% vs 26.4%), and chromaturia (23.1% vs 0.0%). Analysis using a COX proportional hazard model showed that baseline interleukin 6 (IL-6) level was associated with survival benefit of TSU-68 (P = 0.012). Conclusions: TSU-68 plus SOX showed a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. Baseline serum IL-6 levels could be prognostic factors for TSU-68 efficacy. Further biomarker analysis is being performed to determine the efficacy of this treatment. Clinical trial information: JapicCTI-111403.

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Time-dependent Induction of Rat Hepatic CYP1A1 and CYP1A2 Expression after Single-dose Administration of the Anti-angiogenic Agent TSU-68

Cited by 11 publications

References 21 publications

3-Aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone, induces biotransformation enzymes in rat kidney and lung

3-Aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone, induces biotransformation enzymes in rat kidney and lung

In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.

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