Determination of CYP3A4 Inducing Properties of Compounds Using a Laboratory-Developed Cell-Based Assay

Seah, Tiong Chai; Tay, Yea Lu; Tan, Heng Kean; Muhammad, Tengku Sifzizul Tengku; Wahab, Habibah A.; Tan, Mei Lan

doi:10.1177/1091581815599335

Cited by 8 publications

(8 citation statements)

References 81 publications

(106 reference statements)

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“…Although lycopene has been shown to upregulate the expression of CYP3A4, a major catabolic enzyme for docetaxel, 39,40 our PK analyses did not show any detrimental drug–drug interaction for the lycopene and docetaxel combination regimen. Instead, we observed that geometric mean docetaxel exposure (AUC inf ) increased by 9.5% and peak concentration ( C max ) increased by 15.1% with co‐administration of lycopene and docetaxel.…”

Section: Discussionmentioning

confidence: 60%

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients

Lilly,

Wu,

et al. 2024

Clinical & Translational Med

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PurposeOur preclinical studies showed that lycopene enhanced the anti‐prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer.MethodsSubjects were treated with 21‐day cycles of 75 mg/m2 docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel and multiple correlative studies were carried out.ResultsTwenty‐four participants were enrolled, 18 in a dose escalation cohort to define the maximum tolerated dose (MTD), and six in a pharmacokinetic cohort. Docetaxel/ADT plus 150 mg/day synthetic lycopene resulted in dose‐limiting toxicity (pulmonary embolus) in one out of 12 participants with an estimated probability of .106 and thus was chosen as the MTD. Lycopene increased the AUCinf and Cmax of plasma docetaxel by 9.5% and 15.1%, respectively. Correlative studies showed dose‐related changes in circulating endothelial cells and vascular endothelial growth factor A, and reduction in insulin‐like growth factor 1R phosphorylation, associated with lycopene therapy.ConclusionsThe combination of docetaxel/ADT and synthetic lycopene has low toxicity and favourable pharmacokinetics. The effects of lycopene on biomarkers provide additional support for the toxicity‐dependent MTD definition.Highlights The maximum tolerated dose was identified as 150 mg/day of lycopene in combination with docetaxel/ADT for the treatment of metastatic prostate cancer patients. Small increases in plasma exposure to docetaxel were observed with lycopene co‐administration. Mechanistically significant effects were seen on angiogenesis and insulin‐like growth factor 1 signalling by lycopene co‐administration with docetaxel/ADT.

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Section: Discussionmentioning

confidence: 60%

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients

Lilly,

Wu,

et al. 2024

Clinical & Translational Med

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Section: Discussionmentioning

confidence: 99%

“…However, reports of reporter assay directly targeted hepatic CYP3A4 in herbal supplements are limited. It was reported that resveratrol induced the CYP3A4 transcriptional activity in HepG2 cells transfected with a GFP reporter vector (inserted CYP3A4 gene region, −1108 to +54 bp), although CYP3A4 inducers (Dex, omeprazole and Rif) did not upregulate the response dose dependently (Seah et al, 2015). Kim et al (2004) reported that Rif did not induce CYP3A4 transcriptional activity in HepG2 cells transfected with a pCYP3A4-Luc vector (inserted CYP3A4 gene region, −863 to +64 bp), whereas the cells transfected with the vector and steroid and xenobiotic receptor vectors responded to Rif treatment similar to our results.…”

Section: F I G U R Ementioning

confidence: 99%

“…However, there is no simple and stable cell‐based assay for screening CYP3A4 induction. Although there are reporter assays of CYP3A4 transcriptional activity detecting the action of a physiologically active substance using the activation of a targeted gene, a standard method has not been established (Rodríguez‐Antona et al., 2003; Takada et al., 2004; Seah et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

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Safety assessment of herbal supplement components targeting hepatotoxicity and CYP3A4 induction in cell‐based assay using HepG2 cells

Kondo

Suzuki

Chiba

et al. 2022

Journal of Food Science

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Herbal supplements can cause hepatotoxicity and drug interactions via hepatic cytochrome P‐450 (CYP) in some cases. However, there is no simple and stable cell‐based assay to conduct a screening for hepatotoxicity and CYP induction. In the present study, we selected 14 components of the herbal supplement based on our previous reports and investigated the safety of the herbal supplement components focusing on toxicity and CYP3A4 induction in a cell‐based assay using HepG2. The toxicity of the components was examined by lactate dehydrogenase (LDH) and cell proliferation assays. Then, the CYP3A4 induction of the components were examined by a reporter assay using reporter vectors of CYP3A4. The vector includes the CYP3A4 proximal promoter (CYP3A4PP) and the xenobiotic‐responsive enhancer module (XREM) regions. Luteolin (LU) significantly increased LDH activity and decreased cell proliferation activity that suggests LU may cause toxicity in HepG2 cells. Quercetin (QU) increased the transcriptional activity of CYP3A4 (1.5‐fold of control) in the reporter assay. However, the induction of QU was slightly in comparison to the validation of the transcriptional activity of CYP3A4 treated with CYP3A4 inducers. The CYP3A4 induction of QU may not involve CYP3A4PP but involves the XREM response. Throughout our results, the method in the present study may be useful for a safety assessment of herbal supplements, primarily focusing on hepatotoxicity and CYP3A4 induction. Practical Application Even though there are problems with herbal supplements, studies related to toxicity are not actively carried out. The present methods may apply to the safety assessment for herbal supplements and be useful for the prevention and verification of health hazards caused by herbal supplements (the summary is shown in Figure S2).

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“…In addition, other in vitro investigations of CYP isoforms have revealed the inhibitory effects of curcumin and other curcuminoids [ 127 184 , 186 , 187 , 190 , 192 , 198 , 199 ]. Several additional studies utilizing intestinal human colon cancer cell lines, human hepatocytes, and HepG2 cells likewise failed to find any significant effects of curcumin on the mRNA expression of CYP3A4 [ 181 , 200 – 202 ]. The CYP3A4 isoform is the most notable CYP in that it is the primary drug-metabolizing enzyme in liver and intestinal tissue, catalysing the metabolism of half of all commercially available pharmaceuticals [ 203 – 205 ].…”

Section: Introductionmentioning

confidence: 99%

Complementary medicines used in ulcerative colitis and unintended interactions with cytochrome P450-dependent drug-metabolizing enzymes

Şen¹

2022

Turkish Journal of Medical Sciences

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Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disease with multiple genetic and a variety of environmental risk factors. Although current drugs significantly aid in controlling the disease, many people have led to the application of complementary therapies due to the common belief that they are natural and safe, as well as due to the consideration of the side effect of current drugs. Curcumin, cannabinoids, wheatgrass, Boswellia, wormwood and Aloe vera are among the most commonly used complementary medicines in UC. However, these treatments may have adverse and toxic effects due to unintended interactions with drugs or drug-metabolizing enzymes such as cytochrome P450s; thus, being ignorant of these interactions might cause deleterious effects with severe consequences. In addition, the lack of complete and controlled long-term studies with the use of these complementary medicines regarding drug metabolism pose additional risk and unsafety. Thus, this review aims to give an overview of the potential interactions of drug-metabolizing enzymes with the complementary botanical medicines used in UC, drawing attention to possible adverse effects.

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Determination of CYP3A4 Inducing Properties of Compounds Using a Laboratory-Developed Cell-Based Assay

Cited by 8 publications

References 81 publications

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients

Safety assessment of herbal supplement components targeting hepatotoxicity and CYP3A4 induction in cell‐based assay using HepG2 cells

Complementary medicines used in ulcerative colitis and unintended interactions with cytochrome P450-dependent drug-metabolizing enzymes

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