Cytochrome P450 3A (CYP3A) has been extensively studied in humans, but its characterization in cattle is still incomplete. Comparatively, bovine CYP3A is a minor contributor to drug metabolism, despite its constitutive expression in liver, gut and other tissues. Several factors influence cattle CYP3A expression and function: species, breed, age, gender, induction and inhibition phenomena that may lead to drug-drug interactions (DDIs). Marker substrates are testosterone, ethylmorphine and macrolides, but luciferin IPA and midazolam have been recently used, too. Three CYP3A isoforms have been identified in cattle liver (CYP3A28, 3A38 and 3A48) but their tissue distribution and substrate specificities are currently unclear. In humans, CYP3A polymorphisms (SNPs) are sources of individual differences in disease risk and treatment response. Sequencing of CYP3A coding regions in Piedmontese cattle revealed 12 SNPs, whose relevance is now under investigation. At present, no data about intron and splicing variant SNPs are available, but some CYP3A28 SNPs have been associated with productive traits. Species-differences exist in CYP3A regulation, and similar data have been reported for cattle. Following sequencing and in silico analysis of CYP3A28 promoter (~10000 bp 5´ upstream), clusters relevant for CYP3A28 proximal promoter transactivation, resembling those known for CYP3A4, have been identified. Functional studies are currently ongoing. Additional studies on cattle CYP3A are needed to: i) set up and validate in vitro tools useful for in-depth molecular studies; ii) clarify expression and regulation phenomena; iii) find out likely relationships with drug transporters; iv) avoid harmful DDIs. Grants: 2009ZE5HJP (MIUR); CPDA109434, 60A08-7517/13 (University of Padua).
Understanding the mechanism of cattle CYP3A: recent advances and remaining problems
DACASTO, MAURO;ZANCANELLA, VANESSA;GIANTIN, MERY
2014
Abstract
Cytochrome P450 3A (CYP3A) has been extensively studied in humans, but its characterization in cattle is still incomplete. Comparatively, bovine CYP3A is a minor contributor to drug metabolism, despite its constitutive expression in liver, gut and other tissues. Several factors influence cattle CYP3A expression and function: species, breed, age, gender, induction and inhibition phenomena that may lead to drug-drug interactions (DDIs). Marker substrates are testosterone, ethylmorphine and macrolides, but luciferin IPA and midazolam have been recently used, too. Three CYP3A isoforms have been identified in cattle liver (CYP3A28, 3A38 and 3A48) but their tissue distribution and substrate specificities are currently unclear. In humans, CYP3A polymorphisms (SNPs) are sources of individual differences in disease risk and treatment response. Sequencing of CYP3A coding regions in Piedmontese cattle revealed 12 SNPs, whose relevance is now under investigation. At present, no data about intron and splicing variant SNPs are available, but some CYP3A28 SNPs have been associated with productive traits. Species-differences exist in CYP3A regulation, and similar data have been reported for cattle. Following sequencing and in silico analysis of CYP3A28 promoter (~10000 bp 5´ upstream), clusters relevant for CYP3A28 proximal promoter transactivation, resembling those known for CYP3A4, have been identified. Functional studies are currently ongoing. Additional studies on cattle CYP3A are needed to: i) set up and validate in vitro tools useful for in-depth molecular studies; ii) clarify expression and regulation phenomena; iii) find out likely relationships with drug transporters; iv) avoid harmful DDIs. Grants: 2009ZE5HJP (MIUR); CPDA109434, 60A08-7517/13 (University of Padua).
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