Genotype‐phenotype correlations for polymorphisms in cytochrome b5 and NADH cytochrome b5 reductase and hepatic sulfamethoxazole hydroxylamine reduction

Abstract

NADH cytochrome b5 reductase (b5R) and cytochrome b5 (b5) catalyze the reduction of sulfamethoxazole hydroxylamine (SMX‐HA) to the parent drug sulfamethoxazole. SMX‐HA and a spontaneous nitroso metabolite are thought to contribute to sulfonamide hypersensitivity. Variability in SMX‐HA reduction could therefore contribute to the risk of sulfonamide hypersensitivity. The aim of this study was to characterize variability in SMX‐HA reduction in 100 human livers, and determine genotype‐phenotype correlations for polymorphisms in b5R and b5 cDNA. Mean SMX‐HA reduction (200 μM) was 0.59 ± 0.33 nmol/min/mg protein, with a 10‐fold range (0.11–1.23) in 70 livers to date. Vmax for livers with high reduction activity was an order of magnitude higher than livers with low reduction activity.Three individuals were heterozygous for novel single‐nucleotide polymorphisms (SNPs) in either b5R (R59H, R297H) or b5 (S5A). The subject heterozygous for the R297H had low reductase activity (0.21 nmol/min/mg). Two previously reported synonymous b5 SNPs (C35T and G288A; frequencies: 27% and 29% in this population) were found to be in linkage disequilibrium. Work is ongoing to determine the relationship between non‐synonymous SNPs in b5R or b5 and outlier reduction activities.