Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7.
The human cytochromes P450 (P450) CYP3A contribute to the biotransformation of 50% of oxidatively metabolized drugs. The predominant hepatic form is CYP3A4, but recent evidence indicates that CYP3A5 contributes more significantly to the total liver CYP3A than was originally thought. CYP3A7 is the major fetal form and is rarely expressed in adults. To compare the metabolic capabilities of CYP3A forms for 10 substrates, incubations were performed using a consistent molar ratio (1:7:9) of recombinant CYP3A, P450 reductase, and cytochrome b5. A wide range of substrate concentrations was examined to determine the best fit to kinetic models for metabolite formation. In general, K(m) or S(50) values for the substrates were 3 to 4 times lower for CYP3A4 than for CYP3A5 or CYP3A7. For a more direct comparison of these P450 forms, clearance to the metabolites was determined as a linear relationship of rate of metabolite formation for the lowest substrate concentrations examined. The clearance for 1'-hydroxy midazolam formation at low substrate concentrations was similar for CYP3A4 and CYP3A5. For CYP3A5 versus CYP3A4, clearance values at low substrate concentrations were 2 to 20 times lower for the other biotransformations. The clearance values for CYP3A7-catalyzed metabolite formation at low substrate concentrations were substantially lower than for CYP3A4 or CYP3A5, except for clarithromycin, 4-OH triazolam, and N-desmethyl diltiazem (CYP3A5 - CYP3A7). The CYP3A forms demonstrated regioselective differences in some of the biotransformations. These results demonstrate an equal or reduced metabolic capability for CYP3A5 compared with CYP3A4 and a significantly lower capability for CYP3A7.
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
J Andrew
JA
Williams
Barbara J
BJ
Ring
Varon E
VE
Cantrell
David R
DR
Jones
James
J
Eckstein
Kenneth
K
Ruterbories
Mitchell A
MA
Hamman
Stephen D
SD
Hall
Steven A
SA
Wrighton
D000525:Alprazolam / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001711:Biotransformation; D017291:Clarithromycin / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000378:metabolism; D004110:Diltiazem / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008874:Midazolam / Q000378:metabolism; D009543:Nifedipine / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D014229:Triazolam / Q000378:metabolism
C419147:7-benzyloxy-4-trifluoromethylcoumarin; D003374:Coumarins; D013629:Tamoxifen; D014229:Triazolam; D013739:Testosterone; D004958:Estradiol; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem; D017291:Clarithromycin; D009543:Nifedipine; D008874:Midazolam; D000525:Alprazolam