Urinary porphyrins as biological indicators of oxidative stress in the kidney. Interaction of mercury and cephaloridine.
Reduced porphyrins (hexahydroporphyrins, porphyrinogens) are readily oxidized in vitro by free radicals which are known to mediate oxidative stress in tissue cells. To determine if increased urinary porphyrin concentrations may reflect oxidative stress to the kidney in vivo, we measured the urinary porphyrin content of rats treated with mercury as methyl mercury hydroxide (MMH) or cephaloridine, both nephrotoxic, oxidative stress-inducing agents. Rats exposed to MMH at 5 ppm in the drinking water for 4 weeks showed a 4-fold increase in 24-hr total urinary porphyrin content and a 1.3-fold increase in urinary malondialdehyde (MDA), an established measure of oxidative stress in vivo. Treatment with cephaloridine alone (10-500 mg/kg, i.p.) produced a dose-related increase in urinary MDA and total porphyrin levels up to 1.6 and 7 times control values, respectively. Injection of MMH-treated rats with cephaloridine (500 mg/kg) caused a synergistic (20-fold) increase in urinary porphyrin levels, but an additive (1.9-fold) increase in the MDA concentration. Studies in vitro demonstrated that cephaloridine stimulated the iron-catalyzed H2O2-dependent oxidation of porphyrinogens to porphyrins in the absence of either microsomes or mitochondria. Additionally, porphyrinogens were oxidized to porphyrins in an iron-dependent microsomal lipid peroxidation system. Moreover, porphyrinogens served as an effective antioxidant (EC50 approximately 1-2 microM) to lipid peroxidation. These results demonstrate that MMH and cephaloridine synergistically, as well as individually, promote increased oxidation of reduced porphyrins in the kidney and that this action may be mechanistically linked to oxidative stress elicited by these chemicals. Increased urinary porphyrin levels may, therefore, represent a sensitive indicator of oxidative stress in the kidney in vivo.
Miller
D M
DM
Department of Environmental Health, University of Washington, Seattle 98195.
Woods
J S
JS
D000818:Animals; D002509:Cephaloridine / Q000633:toxicity*; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D015227:Lipid Peroxidation; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D011166:Porphyrins / Q000652:urine*; D051381:Rats; D011916:Rats, Inbred F344
D008767:Methylmercury Compounds; D011166:Porphyrins; C020771:methylmercury hydroxide; D002509:Cephaloridine