title: In silico and in vitro pharmacogenetic analysis in mice.
abstract: 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.
authors.affiliation: Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, CA 94304, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.forename: Erin
authors.initials: E
authors.lastname: Farrell
authors.forename: Xun
authors.initials: X
authors.lastname: Zhang
authors.forename: Paul
authors.initials: P
authors.lastname: Weller
authors.forename: Mario
authors.initials: M
authors.lastname: Monshouwer
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wang
authors.forename: Guochun
authors.initials: G
authors.lastname: Liao
authors.forename: Zhaomei
authors.initials: Z
authors.lastname: Zhang
authors.forename: Steven
authors.initials: S
authors.lastname: Hu
authors.forename: John
authors.initials: J
authors.lastname: Allard
authors.forename: Steve
authors.initials: S
authors.lastname: Shafer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Usuka
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
mesh_terms: 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*
chemical_list: 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