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Background  Intervertebral disc degeneration, one of the major causes of low-back pain, results from altered biosynthesis/turnover of extracellular matrix in the disc. Previously, we reported that the analgesic drug Neurotropin® (NTP) had an anabolic effect on glycosaminoglycan synthesis in cultured nucleus pulposus (NP) cells via the stimulation of chondroitin sulfate  N -acetylgalactosaminyltransferase 1. However, its effect on the aggrecan core protein was not significantly detected, because of the data variance. A microarray analysis suggested that the effect of NTP on aggrecan was correlated with  N -acetyltransferase 2 (NAT2), a drug-metabolizing enzyme. Specific  NAT2  alleles are known to correlate with rapid, intermediate, and slow acetylation activities and side effects of various drugs. We investigated the association between the efficacy of NTP on aggrecan expression and the  NAT2  genotype in cell donors.    Methods  NP cells were isolated from intervertebral disc tissues donated by 31 Japanese patients (28–68 years) who underwent discectomy. NTP was added to the primary cell cultures and its effect on the aggrecan mRNA was analyzed using real-time quantitative PCR. To assess acetylator status, genotyping was performed based on the inferred  NAT2  haplotypes of five common single-nucleotide polymorphisms using allele-specific PCR.    Results  The phenotype frequencies of  NAT2  in the patients were 0%, 42.0%, and 58.0% for slow, intermediate, and rapid acetylators, respectively. The proportions of responders to NTP treatment (aggrecan upregulation, ≥ 1.1-fold) in the intermediate and rapid acetylators were 76.9% and 38.9%, respectively. The odds ratio of the comparison of the intermediate acetylator status between responders and nonresponders was 5.2 (95% CI 1.06–26.0, P = 0.036), and regarding the 19 male patients, this was 14.0 (95% CI 1.54–127.2,  P  = 0.012). In the 12 females, the effect was not correlated with  NAT2  phenotype but seemed to become weaker along with aging.    Conclusions  An intermediate acetylator status significantly favored the efficacy of NTP treatment to enhance aggrecan production in NP cells. In males, this tendency was detected with higher significance. This study provides suggestive data of the association between  NAT2  variants and the efficacy of NTP treatment. Given the small sample size, results should be further confirmed.

bmc medical genomics

Association of NAT2 genetic polymorphism with the efficacy of Neurotropin® for the enhancement of aggrecan gene expression in nucleus pulposus cells: a pilot study