Missense single nucleotide variants affecting CYP3A catalytic activity are present in Limousine cattle

Abstract

Cytochrome P450 (CYP) 3A is one of the most important subfamily of drug metabolising enzymes. Genetic factors such as breed and allelic variants might modify CYP3A expression and enzyme activity and lead to inter-and intra-individual variability in clinical response or toxicity. Cattle CYP3A gene cluster has been recently re-sequenced in 300 Piedmontese cattle by deep targeted sequencing. Thirteen missense single nucleotide variants (SNVs) were identified, and for five of them an impact on CYP3A activity was demonstrated in vitro. In the present work, we assessed the genetic frequency of these five SNVs in Limousine, a cattle breed widely raised for meat production in Veneto Region. A total of 215 cows were genotyped using specific melting curve assays. Only two missense SNVs out of five, both located on CYP3A28 coding sequence, were detected: rs384467435 and rs454167819. The former mutant allele was present in homozygosis in the 4% of tested cows, while in heterozygosis in the 24% of animals. The second SNV was detected only in heterozygosis in 11 cows out of 215 (i.e. 4.9%). These findings suggest the presence of missense SNVs, proved to halve CYP3A28 catalytic activity, in both Limousine and Piedmontese meat cattle breeds. As a consequence, these SNVs might impact on the kinetics of xenobiotics metabolised by CYP3A, including drugs and natural toxins like ivermectin and aflatoxins, thereby resulting in toxicity or accumulation of harmful residues in foodstuffs. This result paves the way for new considerations on the fate of xenobiotics in cattle farming. HIGHLIGHTS Missense single nucleotide variants affecting CYP3A catalytic activity in vitro are present in Limousine and Piedmontese cattle breeds. Rs384467435 is the only missense single nucleotide variant for which the mutant allele is recorded in homozygosis in approximately 4% of Limousine and Piedmontese cattle. The polymorphisms here detected might affect the kinetics and the toxicity of xenobiotics metabolised by CYP3A in cattle.