A single‐nucleotide polymorphism in the canine cytochrome b₅ reductase (CYB5R3) gene is associated with sulfonamide hypersensitivity and is overrepresented in Doberman Pinschers

Abstract

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.

Pharmacogenomics of poor drug metabolism in greyhounds: Canine P450 oxidoreductase genetic variation, breed heterogeneity, and functional characterization

“…In dogs, the reduction of the reactive sulfonamide hydroxylamine metabolite is catalyzed by cytochrome b 5 , which accepts electrons from cytochrome b 5 reductase and POR. A correlation between a cytochrome b 5 reductase polymorphism and sulfonamide hypersensitivity exists, but hypersensitivity cannot be explained by the polymorphism alone [ 56 , 57 ]. Electron transfer between POR variants and cytochrome b 5 should be examined in the future.…”

A double-blinded randomized placebo-controlled non-inferiority trial protocol for postoperative infections associated with canine pyometra

“… Body weight < 3 kg or > 93 kg Complicated pyometra Shock unresponsive to fluid resuscitation or sepsis Ruptured uterus and/or peritonitis American Society of Anesthesiologists (ASA) physical status class 4–5 Primary disease increasing risk of infection such as Diabetes mellitus Adrenal dysfunction Chronic, severe liver or kidney disease Malignant neoplasia Urinary bladder neoplasia Immunodeficiency Immunosuppressive medication Prednisolone or prednisone > 1 mg/kg/d, or other glucocorticoids with equivalent dosage Ciclosporin > 5 mg/kg/d Azathioprine ≥ 2 mg/kg/d Cytostatics at any dose Doberman Pinscher breed or known hypersensitivity to sulfonamide-trimethoprim compounds [ 37 ] …”

“…Sulfonamide-trimethoprim compounds have been reported to have the following side effects in dogs: polyarthritis, polyuria, vomiting, inappetence, diarrhoea, fever, thrombocytopenia, keratoconjunctivitis sicca and aplastic anaemia [ 40 , 41 ]. Hepatitis, anaphylaxis and other hypersensitivity reactions are also possible [ 37 ]. Severe adverse effects associated with sulfonamide-trimethoprim medications are extremely rare when the treatment period is short, such as in this study [ 41 ].…”