Conservation of the coding regions of the glycine N-acyltransferase gene further suggests that glycine conjugation is an essential detoxification pathway

Abstract

Thorough investigation of the glycine conjugation pathway has been neglected. No defect of the glycine conjugation pathway has been reported and this could reflect the essential role of glycine conjugation in hepatic metabolism. Therefore, we hypothesised that genetic variation in the open reading frame (ORF) of the GLYAT gene should be low and that deleterious alleles would be found at low frequencies. This hypothesis was investigated by analysing the genetic variation of the human GLYAT ORF using data available in public databases. We also sequenced the GLYAT ORF of a small cohort of South African Afrikaner Caucasian individuals. In total, data from 1537 individuals was analysed. The two most prominent GLYAT haplotypes in all populations analysed, were S156 (70%) and T17S156 (20%). The S156C199 and S156H131 haplotypes, which have a negative effect on the enzyme activity of a recombinant human GLYAT, were detected at very low frequencies. In the Afrikaner Caucasian cohort a novel Q61L SNP occurring at a high frequency (12%) was detected. The results of this study indicated that the GLYAT ORF is highly conserved and supported the hypothesis that the glycine conjugation pathway is an essential detoxification pathway. These findings emphasise the importance of future investigations to determine the in vivo capacity of the glycine conjugation pathway for the detoxification of benzoate and other xenobiotics.

Keywords: Afrikaner Caucasian; Benzoate; GLYAT SNPs; GLYAT haplotypes; Salicylate; Xenobiotic detoxification.