A single-nucleotide polymorphism in the canine cytochrome b 5 reductase (CYB5R3) gene is associated with sulfonamide hypersensitivity and is overrepresented in Doberman Pinschers

• Published in: Journal of veterinary pharmacology and therapeutics Vol. 41; no. 3; pp. 402 - 408
• Main Authors: Reinhart, J M, Ekena, J, Cioffi, A C, Trepanier, L A
• Format: Journal Article
• Language: English
• Published: England 01.06.2018
• Subjects: Animals; Cytochrome-B Reductase - genetics; Cytochrome-B Reductase - metabolism; Dog Diseases - chemically induced; Dog Diseases - genetics; Dogs; Drug Hypersensitivity - genetics; Drug Hypersensitivity - veterinary; Gene Expression Regulation, Enzymologic; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sulfonamides - adverse effects; adverse drug reaction; idiosyncratic; potentiated sulfonamide; genotype
• ISSN: 0140-7783; 1365-2885
• DOI: 10.1111/jvp.12478

Canine sulfonamide hypersensitivity (HS) has been associated with a variant in the cytochrome b reductase gene (CYB5R3 729A>G), which encodes a drug-detoxifying enzyme. Study objectives were to determine variant allele frequency in Doberman Pinschers (DOBE), a breed which may be predisposed to sulfonamide HS, and to characterize the effects of CYB5R3 729G on gene expression and function. CYB5R3 729A>G allele frequencies were compared between DOBE (n = 24) vs. non-Doberman (non-DOBE; n = 60) dogs. CYB5R3mRNA expression, protein expression, and reduction of sulfamethoxazole hydroxylamine were compared between banked canine liver samples of 729AA vs. GG genotype. The 729G allele was overrepresented in DOBE (1.00) vs. non-DOBE dogs (0.567, p < .0001). mRNA and protein expressions as well as cyt b reductase activity were similar between livers of AA and GG genotype. All Doberman Pinschers in this study were homozygous for CYB5R3 729G, which could contribute to this breed's apparent predisposition to sulfonamide HS. However, CYB5R3 729G does not alter sulfamethoxazole detoxification capacity, so a direct role could not be demonstrated. It is possible that this marker is linked to another contributing variant.