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Quantitative Proteomics of Hepatic Drug-Metabolizing Enzymes and Transporters in Patients With Colorectal Cancer
Areti-Maria Vasilogianni1, Zubida M Al-Majdoub1, Brahim Achour1,2
1Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK.
Abstract:
The impact of liver cancer metastasis on protein abundance of 22 drug-metabolizing enzymes (DMEs) and 25 transporters was investigated using liquid chromatography-tandem accurate mass spectrometry targeted proteomics. Microsomes were prepared from liver tissue taken from 15 healthy individuals and 18 patients with cancer (2 primary and 16 metastatic). Patient samples included tumors and matching histologically normal tissue. The levels of cytochrome P450 (CYPs 2B6, 2D6, 2E1, 3A4, and 3A5) and uridine 5'-diphospho-glucuronosyltransferases (UGTs 1A1, 1A6, 1A9, 2B15, 2B4, and 2B7) were lower in histologically normal tissue from patients relative to healthy controls (up to 6.6-fold) and decreased further in tumors (up to 21-fold for CYPs and 58-fold for UGTs). BSEP and MRPs were also suppressed in histologically normal (up to 3.1-fold) and tumorous tissue (up to 6.3-fold) relative to healthy individuals. Abundance of OCT3, OAT2, OAT7, and OATPs followed similar trends (up to 2.9-fold lower in histologically normal tissue and up to 16-fold lower in tumors). Abundance of NTCP and OCT1 was also lower (up to 9-fold). Interestingly, monocarboxylate transporter MCT1 was more abundant (3.3-fold) in tumors, the only protein target to show this pattern. These perturbations could be attributed to inflammation. Interindividual variability was substantially higher in patients with cancer. Proteomics-informed physiologically-based pharmacokinetic (PBPK) models of 50 drugs with different attributes and hepatic extraction ratios (Simcyp) showed substantially lower drug clearance with cancer-specific parameters compared with default parameters. In conclusion, this study provides values for decreased abundance of DMEs and transporters in liver cancer, which enables using population-specific abundance for these patients in PBPK modeling.
Insights
Liver cancer metastasis significantly reduces drug-metabolizing enzymes and transporters, impacting drug clearance. This study quanties these changes for improved physiologically-based pharmacokinetic (PBPK) modeling in cancer patients.
Area of Science:
- Pharmacology and Toxicology
- Oncology
- Biochemistry
Background:
- Liver cancer metastasis alters cellular functions, potentially affecting drug disposition.
- Understanding changes in drug-metabolizing enzymes (DMEs) and transporters is crucial for personalized medicine.
Purpose of the Study:
- To investigate the impact of liver cancer metastasis on the protein abundance of DMEs and transporters.
- To quantify these changes in tumor and non-tumor liver tissues from cancer patients.
- To evaluate the effect of these changes on drug clearance using physiologically-based pharmacokinetic (PBPK) models.
Main Methods:
- Targeted proteomics using liquid chromatography-tandem accurate mass spectrometry.
- Analysis of liver tissue microsomes from healthy individuals and liver cancer patients (primary and metastatic).
- Development of PBPK models (Simcyp) incorporating proteomics-derived abundance data.
Main Results:
- Significant decreases in the abundance of major cytochrome P450 (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) in cancer tissues compared to healthy controls.
- Suppression of transporters including BSEP, MRPs, OCT3, OAT2, OAT7, OATPs, NTCP, and OCT1.
- Monocarboxylate transporter MCT1 was the only protein found to be more abundant in tumors.
- PBPK models showed substantially lower drug clearance with cancer-specific parameters.
Conclusions:
- Liver cancer metastasis leads to a significant downregulation of key drug-metabolizing enzymes and transporters.
- These proteomic changes can be leveraged for population-specific PBPK modeling in liver cancer patients.
- Altered protein abundance may be linked to inflammation and contributes to altered drug pharmacokinetics in cancer.
