Cytochromes P450 2F and Genes of Behavioral Traits: Covariations of Expression in the Human Brain and Polymorphism of the Orthologs in Domestic Goats

Abstract

Human cytochrome P450 2F1, as well as its ortholog 2F3 in domestic goat, is considered to be a rather unusual enzyme. The only type of reaction it catalyzes has been described: the conversion of skatole, a product of anaerobic tryptophan metabolism, into a pulmonary toxin. Endogenous substrates of CYP2F are unknown, and although more than 30 years have passed since the discovery of the enzyme, its biological role remains unclear. We hypothesized that the physiological functions of CYP2F can be specifically implemented in the brain, remaining previously unnoticed owing to the high compartmentalization of the organ. Using open data, we studied the covariation of the expression of CYP2F1 and genes for behavioral traits: in the human brain, as well as the polymorphism of their orthologs and CYP2F3 in 180 populations of domestic goats (Capra hircus). Two SNPs were found in the CYP2F3 gene, one of which had pronounced traces of selection, and the frequency of homozygotes increased with geographic distance from the center of domestication. Expression of CYP2F1 mRNA in the human brain also had regional specificity. In both species, factor analysis revealed the relationship between CYP2F1/3 and a number of genes regulating behavior: the serotonin transporter SLC6A4 and its receptor HTR2A3, the ABCB1 transporter, the purine receptor P2RX7, the GABA receptor GABRA4, the circadian rhythm regulator PER3, and T-cadherin CDH13. Thus, analysis of the genomic data of the domestic goat and human transcriptomic data revealed the evolutionary and functional relationships of CYP2F cytochromes and neurochemical systems for regulating behavior. This evidence of the cerebral function of the enzyme is indirect, since it is based on correlation analysis, but indicates the promise of further search in this direction.