title: Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice.
abstract: Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.
authors.affiliation: Biological Sciences, Clemson University, Clemson, SC, United States of America.
authors.forename: Ramiya
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Environmental Toxicology, Clemson University, Pendleton, SC, United States of America.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Mota
authors.affiliation: Biological Sciences, Clemson University, Clemson, SC, United States of America.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Litoff
authors.affiliation: NHEERL, US-EPA, Research Triangle Park, NC, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Rooney
authors.affiliation: Biological Sciences, Clemson University, Clemson, SC, United States of America.
authors.forename: W Tyler
authors.initials: WT
authors.lastname: Boswell
authors.affiliation: Biological Sciences, Clemson University, Clemson, SC, United States of America.
authors.forename: Elliott
authors.initials: E
authors.lastname: Courter
authors.affiliation: Biological Sciences, Clemson University, Clemson, SC, United States of America.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Henderson
authors.affiliation: Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Hernandez
authors.affiliation: NHEERL, US-EPA, Research Triangle Park, NC, United States of America.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Corton
authors.affiliation: Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.affiliation: Biological Sciences, Clemson University, Clemson, SC, United States of America.|Environmental Toxicology, Clemson University, Pendleton, SC, United States of America.
authors.forename: William S
authors.identifier: http://orcid.org/0000-0002-9491-3403
authors.initials: WS
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D064113:CRISPR-Cas Systems; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D002620:Pharmacological and Toxicological Phenomena; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; C000622269:cytochrome P-450 2B13, mouse; C101679:Cyp2b10 protein, mouse; C121503:Cyp2b9 protein, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins