Factors affecting cytochrome P-450 3A activity in cancer patients.
OBJECTIVE
The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients.


METHODS
A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6).


RESULTS
CYP3A activity (AUC(0-40 min)) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by approximately 50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, alpha-1 acid glycoprotein, explained approximately 18% of overall variation in CYP3A activity (P < 0.001).


CONCLUSIONS
These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.
Baker
Sharyn D
SD
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-1000, USA. sdbaker@jhmi.edu
van Schaik
Ron H N
RH
Rivory
Laurent P
LP
Ten Tije
Albert J
AJ
Dinh
Kimberly
K
Graveland
Wilfried J
WJ
Schenk
Paul W
PW
Charles
Kellie A
KA
Clarke
Stephen J
SJ
Carducci
Michael A
MA
McGuire
William P
WP
Dawkins
Fitzroy
F
Gelderblom
Hans
H
Verweij
Jaap
J
Sparreboom
Alex
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049628:Body Size; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D003710:Demography; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D009961:Orosomucoid / Q000378:metabolism; D010641:Phenotype
D004273:DNA, Neoplasm; D007527:Isoenzymes; D009961:Orosomucoid; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human