The Effect of Methylmalonic Acid Treatment on Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function.

Methylmalonic acidemia is an inborn metabolic disease of propionate catabolism, biochemically characterized by accumulation of methylmalonic acid (MMA) to millimolar concentrations in tissues and body fluids. However, MMA's role in the pathophysiology of the disorder and its status as a "toxic intermediate" is unclear, despite evidence for its ability to compromise antioxidant defenses and induce mitochondrial dysfunction. Coenzyme Q10 (CoQ10) is a prominent electron carrier in the mitochondrial respiratory chain (MRC) and a lipid-soluble antioxidant which has been reported to be deficient in patient-derived fibroblasts and renal tissue from an animal model of the disease. However, at present, it is uncertain which factors are responsible for inducing this CoQ10 deficiency or the effect of this deficit in CoQ10 status on mitochondrial function. Therefore, in this study, we investigated the potential of MMA, the principal metabolite that accumulates in methylmalonic acidemia, to induce a cellular CoQ10 deficiency. In view of the severe neurological presentation of patients with this condition, human neuroblastoma SH-SY5Y cells were used as a neuronal cell model for this investigation. Following treatment with pathological concentrations of MMA (>0.5 mM), we found a significant (p = 0.0087) ~75% reduction in neuronal cell CoQ10 status together with a significant (p = 0.0099) decrease in MRC complex II-III activity at higher concentrations (>2 mM). The deficits in neuronal CoQ10 status and MRC complex II-III activity were associated with a loss of cell viability. However, no significant impairment of mitochondrial membrane potential (ΔΨm) was detectable. These findings indicate the potential of pathological concentrations of MMA to induce a neuronal cell CoQ10 deficiency with an associated loss of MRC complex II-III activity. However, in the absence of an impairment of ΔΨm, the contribution this potential deficit in cellular CoQ10 status makes towards the disease pathophysiology methylmalonic acidemia has yet to be fully elucidated.

Comparative analysis of the influence of clinical factors including BMI on adalimumab and infliximab trough levels.

INTRODUCTION: Optimal trough levels of the anti-tumour necrosis factor agents, infliximab and adalimumab, are correlated with clinical remission. Obesity adversely affects response to infliximab and adalimumab, but the influence of BMI on trough levels has not been adequately investigated. We investigated the relationship between clinical variables, including BMI, and trough levels of infliximab and adalimumab. METHODS: This prospective cross-sectional study included patients treated with infliximab and adalimumab on maintenance therapy, with concurrent measurements of trough levels and BMI. The associations between categorical trough levels and clinical variables, including BMI, were estimated. RESULTS: Of the 122 patients included in the study, 80 (66%) were on infliximab and 42 (34%) were on adalimumab. Eighty-three per cent had Crohn's disease and the remainder had ulcerative colitis. None of the clinical variables, including smoking, BMI, concurrent immunosuppression, duration of disease and treatment, were associated with categorical trough levels of infliximab or adalimumab. The effect of BMI did not differ between the two anti-tumour necrosis factor agents, although there was a trend towards a lower trough level in adalimumab-treated patients with a BMI greater than 30 (P=0.09). In infliximab-treated patients, antibodies to infliximab (P<0.001) and a C-reactive protein level of at least 5 mg/dl were associated with trough levels less than 3 µg/ml (P=0.008). CONCLUSION: BMI does not differentially influence trough levels of adalimumab and infliximab, although a trend towards a lower trough level was observed in adalimumab-treated patients with a BMI greater than 30. Raised C-reactive protein levels and antibodies to infliximab were associated with subtherapeutic levels of infliximab.