Evaluation of effects of copper histidine on copper transporter 1-mediated accumulation of platinum and oxaliplatin-induced neurotoxicity in vitro and in vivo.

The purpose of the present study was to determine whether copper histidine could inhibit copper transporter 1 (Ctr1)-mediated transport of oxaliplatin in vitro and thereby limit the accumulation of platinum and neurotoxicity of oxaliplatin in dorsal root ganglion (DRG) tissue in vivo. In HEK293 cells overexpressing rat Ctr1, copper histidine was shown to be transported by Ctr1 and to inhibit their Ctr1-mediated uptake of oxaliplatin. Pilot in vivo dose-finding studies showed that copper histidine at doses up to 2 mg/kg, p.o., daily for 5 days/week could be added to maximum tolerated doses of oxaliplatin (1.85 mg/kg, i.p., twice weekly) for 8 week combination treatment studies in female Wistar rats. After treatment, rats showed significant changes in sensory neuron size profiles in DRG tissue induced by oxaliplatin that were not altered by its coadministration with copper histidine. The expression of copper transporters (Ctr1 and copper-transporting P-type ATPase 1 (Atp7a)) in DRG tissue appeared unchanged following treatment with oxaliplatin given alone or with copper histidine. Platinum and copper tissue levels were higher in DRG than in most other tissues, but were unaltered by the addition of copper histidine to oxaliplatin treatment. In conclusion, copper histidine inhibited cellular uptake of oxaliplatin mediated by Ctr1 in vitro without altering the accumulation of platinum or neurotoxicity of oxaliplatin in DRG tissue in vivo at doses tolerated in combination with oxaliplatin treatment.

Alpha-lipoic acid supplementation and diabetes.

Diabetes is a common metabolic disorder that is usually accompanied by increased production of reactive oxygen species or by impaired antioxidant defenses. Importantly, oxidative stress is particularly relevant to the risk of cardiovascular disease. Alpha-lipoic acid (LA), a naturally occurring dithiol compound, has long been known as an essential cofactor for mitochondrial bioenergetic enzymes. LA is a very important micronutrient with diverse pharmacologic and antioxidant properties. Pharmacologically, LA improves glycemic control and polyneuropathies associated with diabetes mellitus; it also effectively mitigates toxicities associated with heavy metal poisoning. As an antioxidant, LA directly terminates free radicals, chelates transition metal ions, increases cytosolic glutathione and vitamin C levels, and prevents toxicities associated with their loss. These diverse actions suggest that LA acts by multiple mechanisms both physiologically and pharmacologically. Its biosynthesis decreases as people age and is reduced in people with compromised health, thus suggesting a possible therapeutic role for LA in such cases. Reviewed here is the known efficacy of LA with particular reference to types 1 and 2 diabetes. Particular attention is paid to the potential benefits of LA with respect to glycemic control, improved insulin sensitivity, oxidative stress, and neuropathy in diabetic patients. It appears that the major benefit of LA supplementation is in patients with diabetic neuropathy.

Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress.

alpha-Lipoic acid (LA), a naturally occurring dithiol compound, has long been known as an essential cofactor for mitochondrial bioenergetic enzymes. Aside from its enzymatic role, in vitro and in vivo studies suggest that LA also acts as a powerful micronutrient with diverse pharmacologic and antioxidant properties. Pharmacologically, LA improves glycemic control, polyneuropathies associated with diabetes mellitus, and effectively mitigates toxicities associated with heavy metal poisoning. As an antioxidant, LA directly terminates free radicals, chelates transition metal ions (e.g. iron and copper), increases cytosolic glutathione and vitamin C levels and prevents toxicities associated with their loss. These diverse actions suggest that LA acts by multiple mechanisms both physiologically and pharmacologically, many of which are only now being explored. Herein, we review the known biochemical properties of LA with particular reference to how LA may be an effective agent to ameliorate certain pathophysiologies of many chronic diseases.