In silico and in vitro pharmacogenetic analysis in mice.
Combining the experimental efficiency of a murine hepatic in vitro drug biotransformation system with in silico genetic analysis produces a model system that can rapidly analyze interindividual differences in drug metabolism. This model system was tested by using two clinically important drugs, testosterone and irinotecan, whose metabolism was previously well characterized. The metabolites produced after these drugs were incubated with hepatic in vitro biotransformation systems prepared from the 15 inbred mouse strains were measured. Strain-specific differences in the rate of 16 alpha-hydroxytestosterone generation and irinotecan glucuronidation correlated with the pattern of genetic variation within Cyp2b9 and Ugt1a loci, respectively. These computational predictions were experimentally confirmed using expressed recombinant enzymes. The genetic changes affecting irinotecan metabolism in mice mirrored those in humans that are known to affect the pharmacokinetics and incidence of adverse responses to this medication.
Guo
Yingying
Y
Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, CA 94304, USA.
Lu
Peng
P
Farrell
Erin
E
Zhang
Xun
X
Weller
Paul
P
Monshouwer
Mario
M
Wang
Jianmei
J
Liao
Guochun
G
Zhang
Zhaomei
Z
Hu
Steven
S
Allard
John
J
Shafer
Steve
S
Usuka
Jonathan
J
Peltz
Gary
G
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice / Q000235:genetics*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010597:Pharmacogenetics / Q000379:methods*; D011994:Recombinant Proteins / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000031:analogs & derivatives / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D011994:Recombinant Proteins; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C121503:Cyp2b9 protein, mouse; D000072467:Cytochrome P450 Family 2; D014453:Glucuronosyltransferase