The combination of nuclear and mitochondrial mutations as a risk factor for idiosyncratic toxicity

Dapsone‐Associated Methemoglobinemia in a Patient With Slow NAT2*5B Haplotype and Impaired Cytochrome b5 Reductase Activity

“…37 A recent study of a patient with rash and arthralgia following TMP-SMX administration found a homozygous NAT2*5B genotype, as in our patient, and null GSTM1 and GSTT1 genotypes. 38 Since GSTs are not involved in SMX disposition 39 and have not been reported in association with dapsone clearance, we did not genotype for these null variants. However, it is possible that null mutations in either gene may have predisposed our patient to dapsone methemoglobinemia.…”

The Metabolic Rationale for a Lack of Cross-reactivity Between Sulfonamide Antimicrobials and Other Sulfonamide-containing Drugs

“…Lee et al, showed a greater amount of sulfamethoxazole hydroxylamine in the urine of HIVinfected individuals with hypersensitivity compared to those without hypersensitivity [13]. We then observed that the homozygous extensive metabolizer genotype (CYP 2C9*1/*1) was present in a patient with a concomitant mitochondrial mutation who had a history of hypersensitivity to sulfamethoxazole [15]. We then observed that the homozygous extensive metabolizer genotype (CYP 2C9*1/*1) was present in a patient with a concomitant mitochondrial mutation who had a history of hypersensitivity to sulfamethoxazole [15].…”

“…The likely culprit for this toxicity was subsequently determined to be the [-nitroso] intermediate, generated by the autooxidation of sulfamethoxazole. disease (HIV) and by certain genetic mutations in mitochondria result in a marked alteration in the cellular redox state manifested by a significant decrease in the normal favorable ratio of reduced to oxidized glutathione [15,18]. 3) [17].…”

“…3) [17]. The specific mutation of TC at 11204 in the ND4 subunit of respiratory complex I (C1) in mitochondrial DNA, causes oxidative stress by the inhibition of cellular respiration to increase the formation of reactive oxygen species, thereby decreasing the ratio of reduced to oxidized glutathione; similar to the effect of the HIV tat protein [15,20]. For HIV, the extent of intracellular retrovirus replication generates a large burden of the Tat viral protein that, in turn, causes oxidative stress through inhibition of superoxide dismutase to cause a greater amount of glutathione to exist in the oxidized form, as shown in Fig.…”

“…disease (HIV) and by certain genetic mutations in mitochondria result in a marked alteration in the cellular redox state manifested by a significant decrease in the normal favorable ratio of reduced to oxidized glutathione [15,18]. (3), reaction 3], the presence of the homozygous (double null) mutation of the phase II drug metabolizing enzyme, glutathione-S-transferase (GSTM1*0/*0, GSTT1*0/*0) results in a lack of functional enzymatic activity [15,21]. (4) [19].…”