Article Figures & Data
Figures
- Figure 1
Representative kinetic plots showing Michaelis-Menten hyperbolic kinetic profile (A), sigmoidal autoactivation profile (B), substrate inhibition profile (C), and biphasic kinetic profile (D).
Insets show corresponding Eadie-Hofstee plots for each kinetic profile.
Tables
- Table 1
Examples of activation kinetics (heterotropic positive cooperativity) reported in the literature in various in vitro systems
Effector Substrate Pathway Enzyme Source Reference 7,8-Benzoflavone Aflatoxin B1 8,9-Epoxidation E. coli-purified CYP3A4 Ueng et al., 1997 7,8-Benzoflavone Carbamazepine 10,11-Epoxidation E. coli-purified CYP3A4 Ibid. 7,8-Benzoflavone Phenanthrene Hydroxylation HepG2-expressed CYP3A4 Shou et al., 1994 7,8-Benzoflavone Phenanthrene Hydroxylation HepG2-expressed CYP3A4 Korzekwa et al., 1998 7,8-Benzoflavone Benzo[a]pyrene Hydroxylation RLM Wiebel et al., 1971 7,8-Benzoflavone Benzo[a]pyrene Hydroxylation HLM Kapitulnik et al., 1977 7,8-Benzoflavone Progesterone 6β-Hydroxylation HLM Schwab et al., 1988 7,8-Benzoflavone 17β-Estradiol 2-Hydroxylation HLM Ibid. 7,8-Benzoflavone Diazepam Hydroxylation HLM Andersson et al., 1994 7,8-Benzoflavone Diazepam N-Demethylation HLM Ibid. 7,8-Benzoflavone Phenacetin O-Deethylation HLM Nakajima et al., 1999 Dapsone Flurbiprofen 4′-Hydroxylation Baculovirus-purified CYP2C9 Korzekwa et al., 1998 Dapsone Flurbiprofen 4′-Hydroxylation Baculovirus-expressed CYP2C9 Hutzler et al., 2001b Dapsone Naproxen O-Demethylation Baculovirus-expressed CYP2C9 Ibid. Dapsone Piroxicam 5′-Hydroxylation Baculovirus-expressed CYP2C9 Ibid. Quinidine Meloxicam 5′-Methylhydroxylation HLM and B-lymphoblastoid-expressed CYP3A41-a Ludwig et al., 1999 Quinidine Diclofenac 5-Hydroxylation HLM and B-lymphoblastoid-expressed CYP3A41-a Ngui et al., 2000 Quinidine Warfarin 4′- and 10-hydroxylation HLM and B-lymphoblastoid-expressed CYP3A41-a Ngui et al., 2001 Testosterone Midazolam 4-Hydroxylation HLM and B-lymphoblastoid-expressed CYP3A41-a Wang et al., 2000 Testosterone Diazepam 3-Hydroxylation N-Demethylation B-Lymphoblastoid-expressed CYP3A4 Kenworthy et al., 2001 Testosterone Midazolam 4-Hydroxylation HLM Maenpaa et al., 1998 -
RLM, rat liver microsomes; HLM, human liver microsomes.
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↵1-a Obtained from GENTEST (Woburn, MA).
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Substrate Pathway Enzyme Source Reference Dapsone Hydroxylation Vaccinia-expressed CYP2C9 Korzekwa et al., 1998 Diazepam 3-Hydroxylation Baculovirus-expressed CYP3A4 Shou et al., 1999 Diazepam 3-Hydroxylation B-Lymphoblastoid-expressed CYP3A4 Kenworthy et al., 2001 Diazepam Demethylation Baculovirus-expressed CYP3A4 Shou et al., 1999 Testosterone 16β-Hydroxylation B-Lymphoblastoid-expressed CYP2B62-a Ekins et al., 1998b Testosterone 6β-Hydroxylation B-Lymphoblastoid-expressed CYP3A4 Kenworthy et al., 2001 Acetaminophen O-Glucuronidation HLM Fisher et al., 2000 Estradiol 3-Glucuronidation HLM Ibid. For a more comprehensive review, see Ekins et al. (1998a) orHouston and Kenworthy (2000).
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HLM, human liver microsomes.
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↵2-a Obtained from GENTEST.
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- Table 3
Substrates reported to display substrate inhibition kinetics in various in vitro systems
Substrate Pathway Enzyme Source Reference Benzyloxyresorufin Resorufin formation Baculovirus-expressed CYP3A4 Lin et al., 2001 Celecoxib Hydroxylation Baculovirus-expressed CYP2C9 Lin et al., 2001 Celecoxib Hydroxylation HLM Tang et al., 2000 Dextromethorphan O-Demethylation Baculovirus-expressed CYP2D6 Lin et al., 2001 Ethoxyresorufin Resorufin formation Baculovirus-expressed CYP1A2 Lin et al., 2001 Fluoxetine Demethylation HLM Stevens and Wrighton, 1993 Fluoxetine Demethylation HLM Ring et al., 2001 Halothane TFA formation3-a cDNA-expressed CYP2E13-a Spracklin et al., 1997 Halothane Bromide formation cDNA-expressed CYP2E13-a Ibid. Progesterone 6β-Hydroxylation Baculovirus-expressed CYP3A4 Lin et al., 2001 Tenoxicam 5′-Hydroxylation HLM Zhao et al., 1992 Testosterone 6β-Hydroxylation Baculovirus-expressed CYP3A4 Lin et al., 2001 Triazolam 1′-Hydroxylation HLM Schrag and Wienkers, 2001 -
HLM, human liver microsomes; TFA, trifluoroacetic acid.
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↵3-a Obtained from GENTEST.
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Substrate Pathway Enzyme Source Reference Aminopyrine N-Demethylation Yeast-expressed CYP1A1 Inouye et al., 2000 7-Ethoxycoumarin O-Deethylation Yeast-expressed CYP1A1 Ibid. Levo-α-acetylmethadol Demethylation HLM and cDNA-expressed CYP3A4 Oda and Kharasch, 2001 1-Methoxy-4-nitrobenzene O-Demethylation E. coli-purified CYP1A24-a Miller and Guengerich, 2001 Naphthalene Hydroxylation Baculovirus-expressed CYP3A4 Korzekwa et al., 1998 Naproxen O-Demethylation Vaccinia-expressed CYP2C9 Korzekwa et al., 1998 Naproxen O-Demethylation Baculovirus-expressed CYP2C9 Hutzler et al., 2001b Nor-levo-α-acetylmethadol Demethylation HLM and cDNA-expressed CYP3A4 Ibid. -
HLM, human liver microsomes.
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↵4-a Rabbit enzyme.
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