Mechanism of Action of Panaxytriol on Midazolam 1'-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

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  • He Fang
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics Jiangxi Province Cancer Hospital
  • Zhang Wen
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics
  • Zeng Caiwen
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics Jiangxi Province Cancer Hospital
  • Xia Chunhua
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics
  • Xiong Yuqing
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics
  • Zhang Hong
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics
  • Huang Shibo
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics
  • Liu Mingyi
    Clinical Pharmacology Institute, Nanchang University/Jiangxi Province Key Lab of Clinical Pharmacokinetics

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  • Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

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In our previous study, panaxytriol (PXT) was shown to enhance midazolam (MDZ) 1′-hydroxylation significantly but to inhibit MDZ 4-hydroxylation. To explore the underlying mechanism, we investigated the effects of PXT on cytochrome P450 3A (CYP3A)-mediated MDZ metabolic pathways using rat liver microsomes (RLM), human liver microsomes (HLM), and rat primary hepatocytes. In the presence of PXT, the Vmax of 4-OH MDZ decreased from 0.72 to 0.51 nmol/min·mg pro in RLM and from 0.32 to 0.12 nmol/min·mg pro in HLM, and the Km value increased from 5.12 to 7.26 µM in RLM and from 27.87 to 32.80 µM in HLM. But the presence of PXT reduced the Km and increased the Vmax values of MDZ 1′-hydroxylation in RLM and HLM. Interestingly, the differential effect of PXT on MDZ 4-hydroxylation and 1′-hydroxylation was also observed in primary rat hepatocytes after 45-min culture. PXT did not affect the expression levels of CYP3A1/2 mRNA in rat hepatocytes. With extension of the culture time to 6 h, however, PXT significantly inhibited both MDZ 4-hydroxylation and 1′-hydroxylation, and the expression level of CYP3A1/2 mRNA was decreased to 87% and 80% (CYP3A1) and to 89% and 85% (CYP3A2) of those in controls in the presence of PXT 4.0 and 8.0 µg/mL, respectively. These results suggest that PXT could activate MDZ 1′-hydroxylation but inhibit MDZ 4-hydroxylation by changing the CYP3A enzyme affinity and metabolic rate after a short-term intervention. However, long-term treatment with PXT could inhibit both the 4-hydroxylation and 1′-hydroxylation of MDZ by downregulating CYP3A1/2 mRNA expression.

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