Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Mol Pharm. 2021 Dec 6;18(12):4322-4330. doi: 10.1021/acs.molpharmaceut.1c00490. Epub 2021 Nov 4.
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.
甲状旁腺激素相关蛋白（PTHrP）由肿瘤分泌，促进恶病质的进展，恶病质在一半的癌症患者中观察到。虽然据报道癌症恶病质患者的药物清除率降低，但细节尚未阐明。本研究报告了一项关于 PTHrP 是否参与癌症恶病质病例中药物代谢改变的调查。血清 PTHrP 水平升高的癌症恶病质模型大鼠显示肝和肠 CYP3A2 蛋白表达显著降低。当咪达唑仑（CYP3A 底物药物）静脉注射或口服给予癌症恶病质大鼠时，其 AUC 增加了约 2 倍和 5 倍，与对照组相比。因此，咪达唑仑的生物利用度增加了约 3 倍，从而增强了其药理作用。使用 HepG2 细胞和 Caco-2 细胞的体外实验表明，向每个细胞中添加来自癌症恶病质大鼠的血清或活性 PTHrP（1-34）会导致 CYP3A4 mRNA 的表达显著降低。用细胞通透的 cAMP 类似物处理也会导致 CYP3A4 表达降低。用蛋白激酶 A（PKA）、蛋白激酶 C（PKC）和核因子-κB（NF-κB）抑制剂预处理可恢复 PTHrP（1-34）诱导的 CYP3A4 表达降低。这些结果表明，PTHrP 通过 cAMP/PKA/PKC/NF-κB 途径抑制 CYP3A 表达。因此，PTHrP 可能参与癌症恶病质中观察到的药物代谢变化。
