Fig. 2: Lower HH CYP3A4 activities relative to NADPH-HLM can manifest as disparate CYP phenotyping. | Communications Biology

Fig. 2: Lower HH CYP3A4 activities relative to NADPH-HLM can manifest as disparate CYP phenotyping.

From: A mismatch in enzyme-redox partnerships underlies divergent cytochrome P450 activities between human hepatocytes and microsomes

Fig. 2

A Relative levels of savolitinib metabolites M2 and M4 formed over 1 h by HH and NADPH-HLM after incubation of savolitinib (1 µM) including a comparison of M2 and M4 levels at the 60 min time point. The data represents the mean +SD of three independent determinations and statistical significance was assessed by the unpaired two-tailed t-test with Welch’s correction. B Comparison of the percentage savolitinib remaining after incubating with recombinant CYP1A2-POR (CYP:POR ratio of 1:4.4) and CYP3A4-POR (CYP:POR ratio of 1:4), final CYP concentration in incubation of 100 pmol/mL for 1 h. The data represents the mean +SD of three independent determinations and statistical significance was assessed by the unpaired two-tailed t-test with Welch’s correction. C Comparison of M4 and M2 concentrations after incubating with recombinant CYP1A2-POR and CYP3A4-POR enzymes for 1 h. The data represents the mean +SD of three independent determinations and statistical significance was assessed by the unpaired two-tailed t-test with Welch’s correction. D Effect of specific inhibitors (furafylline, 20 µM, (-)-N-3-benzylphenobarbital, 1 µM) and quinidine, 10 µM) on formation of M2 after incubating savolitinib (1 µM) over 1 h in HH. The data are plotted as the average +SD of three independent determinations. Statistical significance was determined using multiple unpaired t-tests corrected for multiple comparisons using the Holm-Sidak method. Asterisks show statistical significance between savolitinib and savolitinib + furafylline at each time point with the p value for the 60 min time point stated for all inhibitors versus savolitinib alone. E Effect of savolitinib concentration (0.2 µM and 1.0 µM) on the savolitinib metabolite ratios (M4:M2) determined in NADPH-HLM at 37 °C for 1 h. The data represents the mean +SD of three independent determinations and statistical significance was assessed by the unpaired two-tailed t-test with Welch’s correction.

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