Human hepatocytes

Acetonitrile, methanol and DMSO had no apparent effect on umbelliferone glucuronidation in human hepatocytes at concentration up to 2% [32]. With HLMs or expressed UGTs, inhibitory effects of organic solvents on glucuronidation of 7-hydroxy-4-trifluoromethyl-coumarin (7-HFC) and estradiol generally followed the order acetonitrile > ethanol > methonal > DMSO [33], DMSO did not inhibit estradiol-3-glucuronidation activity at a concentration up... 

Easterbrook, J., Liu, C., Sakai, Y. and Li, A.P. (2001) Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes. Drug Metabolism and Disposition The Biological Fate of Chemicals, 29, 141-144. 

Nakai, D., et al. Human liver-specific organic anion transporter, LST-1, mediates uptake of pravastatin by human hepatocytes. J. Pharmacol. Exp. Ther. 2001, 297, 861-867. 

In contrast, some Type II cations, such as N-(4,4-azo-n-pentyl)-21-deoxy-ajmalinium and rocuronium, have been shown to be transported by rat Oatp 2 [64—66]. Since human OATP2 or OATP8 cannot transport organic cations [53], the molecular mechanism for the uptake of Type II cations (e.g., rocuronium) into isolated human hepatocytes [11] remains to be clarified. Although human OATP-A transports rocuronium, its hepatic expression is minimal [66]. 

MDCK II cells (Fig. 12.3) [93], Kinetic analysis revealed that the Km value for transcellular transport (24 pM) was similar to the Km for OATP2 (34 pM) [93], Moreover, the efflux across the bile canalicular membrane was not saturated under these experimental conditions. These in vitro observations are consistent with in vivo experimental results in rats which showed that the rate-determining process for the biliary excretion of pravastatin is uptake across the sinusoidal membrane. By normalizing the expression level between the double transfectant and human hepatocytes, it might be possible to predict in vivo hepatobiliary excretion. 

Sandker, G. W., Weert, B., Olinga, P., Wolters, H., Slooff, M. J., Meijer, D. K., Groothuis, G. M., Characterization of transport in isolated human hepatocytes. A study with the bile add taurocholic add, the uncharged ouabain and the organic... 

Shitara, Y., Lu, C., Li, A. P., Y. Kato, Y., Suzuki, H., Ito, K., Itoh, T., Sugiyama, Y., Cryopreserved human hepatocytes as a tool for the prediction of in vivo transport and transporter-mediated drug-drug interactions, Abstract of International Conference on Drug Interaction, Hamamatsu, October 21-23, 1999, p. 87. 

Kier, L. D. et al., Applications of microarrays with toxicologically relevant genes (tox genes) for the evaluation of chemical toxicants in Sprague Dawley rats in vivo and human hepatocytes in vitro, Mutat. Res., 549, 101, 2004. 

Based on the in vitro results and the rat in vivo studies at different exposure levels, induction of CYP isoforms in human hepatocytes is considerably lower for metofluthrin than phenobarbital at identical concentrations [115, 116]. 

Hirose Y, Nagahori H, Yamada T et al (2009) Comparison of the effects of the synthetic pyrethroid metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes. Toxicology 258 64—69... 

Price RJ, Giddings AM, Scott MP et al (2008) Effect of pyrethrins on cytochrome P450 forms in cultured rat and human hepatocytes. Toxicology 243 84—95... 

Parzefall W, ErberE, Sedivy R et al (1991) Testing for induction of DNA synthesis in human hepatocyte primary cultures by rat liver tumor promoters. Cancer Res 51 1143-1147... 

Guillouzo et al. (1988) developed a coculture system of rat or human hepatocytes with rat liver epithelial cells that maintains the hepatocytes in a differentiated state for extended periods of time, thereby allowing studies involving chronic treatment with the test substance to be conducted. Primary cultures of hepatocytes can therefore provide a useful model for short- and long-term studies involving the safety assessment of xenobiotics. 

Donata, M.T., Gomez-Lechon, M.J. and Castell, J.V (1990). Effect of xenobiotics on monooxygenase activities in cultured human hepatocytes. Biochem. Pharmacol. 8(39) 1321-1326. 

McGinnity, D.F., Berry, A.J., Kenny J.R., Grime, K. and Riley, R.J. (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metabolism and Disposition, 34 (8), 1291-1300. 

Primary hepatocytes are a common in vitro system to evaluate metabolism, toxicity and enzyme induction [67-69]. Human hepatocytes are considered the most relevant system to evaluate or predict human metabolism or effects of a new dmg. A significant... 

Mills, J.B., Rose, K.A., Sadagopan, N., Sahi, J. and de Morais, S.M. (2004) Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. The Journal of Pharmacology and Experimented Therapeutics, 309, 303-309. 

Kocarek, T.A., Schuetz, E.G., Strom, S.C., Fisher, R.A. and Guzelian, P.S. (1995) Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocytes. 

Watanabe R, Tanaka Y. 1982. Age-related alterations in the size of human hepatocytes A study of mononuclear and binucleate cells. Virchows Arch 39 9-20. 

Schuetz EG, Schuetz JD, Strom SC, Thompson MT, Fisher RA, Molowa DT, Li D, Guzelian PS (1993) Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes. Hepatology 18 1254— 1262. 

The reactive mutagens formed from arylamides are hydroxylamines (Fig. 4.8) produced either by deacetylation and subsequent (V-hydroxylation (Pathway a), or by A-hydroxylalion and subsequent deacetylation (Pathway b). An alternative pathway to form A-hydroxyaminofluorene involves transacetylation by A, 0 - acy I Iran sI erase, producing A-acetoxyarylamine (Pathway c). The latter mode of activation seems to operate in human hepatocytes, since... 

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