Although various in vitro assays have been developed to evaluate the cytochrome P450 (CYP)-inducing potential of drug candidates, there is a continuing need for the development of a reliable model in drug discovery. The objective of the present study was to compare CYP induction by chemicals in HepG2 cells with Huh7, NKNT-3, and reverted NKNT-3 cells. HepG2 cells showed more similarity to human liver than the other cell lines in comparisons of the expression of cellular proteins. In evaluation of basal CYP activity, Huh7 cells exhibited the highest CYP1A2 and CYP3A4 activity, and HepG2 cells showed the highest CYP2B6 activity. The inducibility of CYP1A2, CYP2B6, and CYP3A4 by prototypical inducers was determined using enzyme assay, immunoblot analysis, and real-time PCR. Among the cells tested, HepG2 cells were highly responsive to CYP inducers, such as 3-methylcholanthrene for CYP1A2 and phenobarbital for CYP2B6 and CYP3A4. Moreover, HepG2 cells were responsive to various CYP1A2, CYP2B6, and CYP3A4 inducers as determined using fluorogenic and LC-MS/MS substrates. Thus, HepG2 cells may be comparable to human hepatocytes for the evaluation of CYP induction or slightly less sensitive. These results suggest HepG2 cells as a cell-based model in screening for CYP inducers in drug discovery.

These results demonstrate that L-serine ameliorates alcoholic fatty liver by accelerating L-serine-dependent homocysteine metabolism.

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Effects of aging on hepatic expression and activity of cytochrome P450 (CYP) isoforms were investigated in male mice aged 2, 6, 18, and 30 months. Microsomal protein, total CYP, cytochrome b5 and NADPH-dependent cytochrome P450 reductase contents in liver were fully expressed in young (2-month-old) mice. Neither Cyp1a1 nor Cyp2c was detected in any aged mice. And Cyp1a2 was maximally expressed at 2 months and decreased with age. Hepatic levels of Cyp2b10 and Cyp3a11 were decreased in 30-month-old mice. Hepatic Cyp2e1 levels were constantly maintained from 2-month to 30-month old mice. Hepatic activities of ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase were gradually decreased after 6 months. The 30-month-old mice exhibited the lowest activity of midazolam 1'-hydroxylase. Pentoxyresorufin-O-depenthylase activity was decreased in 30-month-old mice, but not statistically significant. There were no significant differences in hepatic activities of chlorzoxazone 6-hydroxylase and midazolam 4-hydroxylase. The present study shows that increasing age, especially 30-month-old mice, leads to decrease in expression and activity of hepatic CYP isoforms, suggesting that aging mice exhibit poor hepatic drug-metabolizing capacity.

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