Involvement of the Parathyroid Hormone-Related Protein on Changes in the CYP3A Expression in Cancer Cachexia

• Published in: Molecular pharmaceutics Vol. 18; no. 12; pp. 4322 - 4330
• Main Authors: Fujita, Issei, Watanabe, Hiroshi, Ikegami, Komei, Imafuku, Tadashi, Ichimizu, Shota, Chikamatsu, Mayuko, Kobayashi, Kazuki, Tanaka, Ryusei, Yamada, Koichi, Maeda, Hitoshi, Maruyama, Toru
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06-12-2021
• Subjects: Animals; Cachexia - metabolism; Caco-2 Cells; Cytochrome P-450 CYP3A - genetics; Hep G2 Cells; Humans; Liver - enzymology; Male; Midazolam - pharmacokinetics; Neoplasms - complications; NF-kappa B - physiology; Parathyroid Hormone-Related Protein - physiology; Protein Kinase C - physiology; Rats; Rats, Sprague-Dawley; pharmacokinetics; PTH receptor; cytochrome P450 3A; midazolam; cancer cachexia; parathyroid hormone-related protein
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.1c00490

Parathyroid hormone-related protein (PTHrP), which is secreted from a tumor, contributes to the progression of cachexia, a condition that is observed in half of all cancer patients. Although drug clearance was reported to decrease in patients with cancer cachexia, the details have not been clarified. The present study reports on an investigation of whether PTHrP is involved in the alternation of drug metabolism in cases of cancer cachexia. Cancer cachexia model rats with elevated serum PTHrP levels showed a significant decrease in hepatic and intestinal CYP3A2 protein expression. When midazolam, a CYP3A substrate drug, was administered intravenously or orally to the cancer cachexia rats, its area under the curve (AUC) was increased by about 2 and 5 times, as compared to the control group. Accordingly, the bioavailability of midazolam was increased by about 3 times, thus enhancing its pharmacological effect. In vitro experiments using HepG2 cells and Caco-2 cells showed that the addition of serum from cancer cachexia rats or active PTHrP (1–34) to each cell resulted in a significant decrease in the expression of CYP3A4 mRNA. Treatment with a cell-permeable cAMP analog also resulted in a decreased CYP3A4 expression. Pretreatment with protein kinase A (PKA), protein kinase C (PKC), and nuclear factor-kappa B (NF-κB) inhibitors recovered the decrease in CYP3A4 expression that was induced by PTHrP (1–34). These results suggest that PTHrP suppresses CYP3A expression via the cAMP/PKA/PKC/NF-κB pathway. Therefore, it is likely that PTHrP would be involved in the changes in drug metabolism observed in cancer cachexia.