Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trout liver homogenates metabolized di-2-ethylhexyl phthalate (DEHP) to monoethylhexyl phthalate (MEHP) without added NADPH and to MEHP and more polar metabolites with added NADPH. Both hydrolysis and oxidative metabolism of DEHP were inhibited by piperonyl butoxide. The 10,000g pellet, 100,000g pellet and 100,000g supernatant fraction from liver homogenates all catalyzed the hydrolysis of DEHP and all but the 100,000g supernatant fraction showed the shift to more polar metabolites with added NADPH; serum also catalyzed the hydrolysis of DEHP. Measurement of the microsomal marker, glucose 6-phosphatase, and the mitochondrial marker, succinic dehydrogenase, revealed that DEHP-hydrolytic activity was associated with microsomes and the 100,000g supernatant fraction, whereas DEHP oxidation was associated only with microsomes.
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PMID:Metabolism of di-2-ethylhexyl phthalate by subcellular fractions from rainbow trout liver. 1 73

There is considerable evidence from in vivo studies that the Sertoli cell is an initial target cell for the actions of phthalates in the rodent testis. Because this metabolically active cell type plays a central role in spermatogenesis, we examined the effects of a toxic phthalate, mono-(2-ethylhexyl)-phthalate (MEHP), on the secretory and synthetic activities of primary testicular cell cultures isolated from 18-day-old rats. These cultures were 78-84% Sertoli cells. Exposure to MEHP decreased cellular ATP by ca. 20%, decreased production of radiolabeled 14CO2 from acetate, and decreased media levels of pyruvate, while it increased media levels of lactate and intracellular lipid. Protein synthesis, evaluated by radiolabeled leucine incorporation, was not affected by MEHP. Mitochondrial succinate dehydrogenase activity was decreased in the presence of MEHP. Michaelis-Menton kinetic analysis indicated this was a mixed inhibition. There was no apparent change in mitochondrial Rhodamine 123 uptake. These data are consistent with the concept that mitochondria are one target for the actions of MEHP in the Sertoli cell.
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PMID:The effects of mono-(2-ethylhexyl)-phthalate on rat Sertoli cell-enriched primary cultures. 335 91

Isolated rat liver mitochondria were exposed to mono- and di-n-butyl phthalate (MBP and DBP) and mono- and di(2-ethylhexyl)phthalate (MEHP and DEHP) and examined for effects on mitochondrial energy-dependent processes, including oxidative phosphorylation and active K+ uptake. Additional studies on the effects of these phthalate esters on succinate oxidation and on mitochondrial membrane integrity are also included. DBP and MEHP stimulated succinate state 4 respiration, impaired K+-valinomycin induced swelling with succinate, ascorbate, or ATP as the energy sources, and inhibited succinate state 3 respiration and succinate cytochrome c reductase activity. MEHP was found to act as a non-competitive inhibitor of succinate dehydrogenase activity, with an apparent Ki = 2.4 X 10(-4) M. At concentrations which uncouple energy linked reactions, MEHP and DBP produced only slight energy-independent swelling and release of soluble proteins from isolated mitochondria. MBP caused only slight stimulation of state 4 respiration and impairment of K+-valinomycin induced swelling with each of the 3 energy sources, however, of the 4 phthalate esters, it produced the greatest energy-independent swelling and led to the greatest release of soluble mitochondrial proteins. DEHP had no apparent effect on any of these processes except for slight impairment of ATP-dependent K+-valinomycin induced swelling. It is concluded that phthalate ester toxicity in liver mitochondria is due to uncoupling of energy linked reactions and/or inhibition of succinate dehydrogenase activity. Uncoupling by MBP may involve disruption of mitochondrial membrane integrity, while uncoupling by DBP and MEHP is probably due to an increase in membrane permeability to H+ and other small ions.
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PMID:Effect of phthalate esters on energy coupling and succinate oxidation in rat liver mitochondria. 396 78

Young male Sprague-Dawley rats and Syrian hamsters were treated with 25-1000 mg/kg/day di-(2-ethylhexyl) phthalate (DEHP) orally for 14 days. Liver enlargement was observed in both species, the magnitude being greater in the rat than in the hamster. In the rat there was a marked dose-dependent induction of the peroxisomal marker cyanide-insensitive palmitoyl-CoA oxidation and also of carnitine acetyltransferase. Little effect was observed on the mitochondrial markers carnitine palmitoyltransferase and succinate dehydrogenase. Whereas in the rat, increased peroxisomal enzyme activities were observed after treatment with 100 and 250 mg/kg/day DEHP, much less effect was observed in the hamster even after 1000 mg/kg/day DEHP. Parallel morphological investigations demonstrated a greater increase in hepatic peroxisome numbers in the rat than in the hamster. 14C-labeled DEHP was found to be more rapidly hydrolyzed by rat than hamster hepatic and small intestinal mucosal cell preparations and differences were also observed in the absorption and excretion of oral doses of [14C]DEHP. Studies with mono-(2-ethylhexyl) phthalate (MEHP), a primary metabolite of DEHP, and a hypolipidemic drug clofibrate also resulted in a greater increase in hepatic peroxisomal enzymes in the rat compared to the hamster. The results demonstrate that while DEHP, MEHP, and clofibrate induced hepatic peroxisome proliferation in both species, there was a marked species difference in response. Comparative long-term studies in these species may thus help to clarify the role of peroxisome proliferation in the hepatocarcinogenicity of DEHP.
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PMID:Comparative studies on di-(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation in the rat and hamster. 671 Apr 84

The effects of mono- and dibutyl phthalate and mono- and di(2-ethylhexyl) phthalate on energy-dependent K+ uptake, respiration rates, and succinate cytochrome c reductase activities of isolated rat liver mitochondria were evaluated. The energy-coupling processes, active K+ transport and oxidative phosphorylation, were affected most by di-n-butyl phthalate and mono(2-ethylhexyl) phthalate. Mono-n-butyl phthalate had a moderate effect on energy coupling and di(2-ethylhexyl) phthalate had no apparent effect. The potency of inhibition of succinate cytochrome c reductase activity was mono(2-ethylhexyl) phthalate greater than di-n-butyl phthalate greater than mono-n-butyl phthalate = di(2-ethylhexyl) phthalate. It is concluded that phthalate esters affect mitochondrial activities by altering the permeability properties of the inner membrane and by inhibiting succinate dehydrogenase activity.
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PMID:Mitochondrial toxicity of phthalate esters. 714 Jun 96