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Published on: July 14, 2023

Tumor-derived Parathyroid Hormone-Related Protein Is Associated with Suppression of Cytochrome P450 Expression:

Issei Fujita1, Tsubasa Kaji2, Isamu Noguchi2

  • 1Department of Clinical Pharmacy and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.

ACS Pharmacology & Translational Science
|August 19, 2026
PubMed

Insights

Tumor-derived parathyroid hormone-related protein (PTHrP) is linked to suppressed drug metabolism in cancer cachexia by downregulating cytochrome P450 (CYP) enzymes. This suggests PTHrP may be a biomarker for altered drug pharmacokinetics.

Area of Science:

  • Pharmacology
  • Oncology
  • Biochemistry

Background:

  • Cancer cachexia often involves altered drug metabolism and increased chemotherapy toxicity.
  • Downregulation of cytochrome P450 (CYP) enzymes contributes to these metabolic changes.
  • The precise molecular mechanisms behind this broad metabolic suppression are not fully understood.

Purpose of the Study:

  • To investigate the association between tumor-derived parathyroid hormone-related protein (PTHrP) and the suppression of multiple CYP enzyme families.
  • To determine if PTHrP contributes to the downregulation of drug-metabolizing enzymes in cancer cachexia.

Main Methods:

  • Utilized a rat cachexia model to assess CYP expression and pharmacokinetics.
  • Conducted in vitro experiments with primary rat hepatocytes and PTHrP treatment.
  • Analyzed human The Cancer Genome Atlas (TCGA) hepatocellular carcinoma (HCC) data.
  • Employed single-cell RNA sequencing and spatial transcriptomics for detailed analysis.

Main Results:

  • Significant downregulation of CYP3A, CYP1A, CYP2C, CYP2D, and CYP2E1 in liver and small intestine of cachectic rats.
  • Increased drug AUC and reduced clearance observed in pharmacokinetic analyses.
  • PTHrP treatment reduced CYP isoform expression in primary rat hepatocytes.
  • Negative correlation between PTHrP and CYP gene expression in human HCC data, linked to NF-κB pathways.
  • PTHrP-high tumor regions showed suppressed xenobiotic metabolism.
  • High tumor PTHrP correlated with reduced CYP expression in adjacent nontumor hepatocytes in liver metastases.

Conclusions:

  • Tumor-derived PTHrP is associated with the suppression of drug-metabolizing CYP enzymes in cancer cachexia.
  • PTHrP is a potential contributing factor to the metabolic suppression observed in cancer patients.
  • PTHrP warrants further investigation as a candidate biomarker for altered drug metabolism and toxicity, requiring mechanistic and clinical validation.
Keywords:
CYPPTHrPcancer cachexiadrug metabolismparathyroid hormone-related proteinpharmacokinetics

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