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PubMed1980

Oxidation of 3-oxygenated delta 4 and delta 5 - C27 steroids by soybean lipoxygenase and rat liver microsomes.

The formation of dioxygenated metabolites of cholesterol, epicholesterol (5-cholesten-3 alpha-ol) 4-cholesten-3 beta-ol, 4-cholesten-3 alpha-one and 4-stigmasten-3-one was studied after incubations with soybean lipoxygenase and linoleic acid. From cholesterol and epicholesterol were formed the 7 alpha-hydroxy, 7 beta-hydroxy-, 7 beta-hydroperoxy-, 7-oxo and 5,6-epoxy-derivatives as well as 6 beta-hydroxy-4-cholesten-3-one. All delta 4-steroids were hydroxylated in the 6 alpha- and 6 beta-positions. The ratios between the yields of 6 beta- and 6 alpha-hydroxylated metabolites varied between 3:1 and 2:1. Incubations with 4-cholesten-3 alpha-ol and 4-cholesten-3 beta-ol also afforded the 4,5-epoxides of these steroids. The ratios between the yields of the 4 beta, 5 beta- and 4 alpha, 5 alpha-epoxides were ca. 4:1 for 4-cholesten 3 beta-ol and ca. 3:2 for 4-cholesten-3 alpha-ol. With iron-supplemented microsomes from rat liver, the compounds formed were qualitatively and quantitatively the same as with soybean lipoxygenase, whereas with 18,000 X g rat liver supernatant fractions the yields of all products formed--except 7 alpha-hydroxycholesterol and 6 beta-hydroxy-4-cholesten-3-one--were markedly decreased. The results indicate the presence of a rat liver microsomal 6 beta-hydroxylase which can use 4-cholesten-3-one as a substrate and extend previous findings of similarities between soybean lipoxygenase and a nonspecific lipoxygenase in rat liver microsomes.

Animals↗

PubMed1985

An improved assay for cholesterol 7 alpha-hydroxylase activity using phospholipid liposome solubilized substrate.

A persistent problem in measurement of cholesterol 7 alpha-hydroxylase (7 alpha-OHase) activity by isotope incorporation has been solubilization of cholesterol substrate. Solubilization with Tween 20, for example, resulted in a 75% reduction in 7 alpha-OHase activity after a 60 min incubation of substrate with microsomes. Incorporation of cholesterol substrate into small, unilamellar phospholipid vesicles (liposomes) prevented this effect, resulting in a 50% increase in activity over the same 60 min incubation at optimal concentrations. Using cholesterol in liposomes as substrate, standard assay conditions were determined to be: preparation of liposomes with 180 microM cholesterol substrate and 0.5 mg phospholipid/assay; incubation of these liposomes with 0.5 mg microsomal protein at 37 C for 60 min; addition of a NADPH generating system to start the reaction, and incubation at 37 C for 30 min before stopping the reaction and determining the amount of 7 alpha-hydroxycholesterol formed. In addition to preventing the detergent-related inhibition of the enzyme, liposome-solubilized substrate also reduced the variation among replicates from a coefficient of 45% with Tween 20 to 4.2% with phospholipid. This method provides a sensitive and reliable alternative to methods which require more sophisticated equipment and allows total control of substrate concentration in a form readily accessible to the enzyme.

Animals↗

PubMed1982

Unusual urinary cholesterol metabolites following intracerebral injection of [4-14C]cholesterol into rats: I. The minor 14C-metabolite.

[4-14C]Cholesterol injected intracerebrally into 10-12-day-old rats becomes localized largely in central nervous system myelin. If sufficient 14C is injected, myelin cholesterol remains labeled for the rest of the rats' lives. In the course of the slow myelin cholesterol turnover that ensues, a unique series of cholesterol metabolites is excreted exclusively in the rats' urine. There is reason to believe that the metabolites are formed in the central nervous system before entering the urine. This manuscript describes separation of the 2 urinary 14C-labeled metabolic types and isolation and identification of the minor 14C-labeled material which consists of cholesterol and 2 other sterols bound covalently to short-chain peptides. The minor sterols have been tentatively identified as 24- and 26-hydroxycholesterol. The sterol-peptide combinations have been isolated from human male urine, also.

Amino Acids↗

PubMed1995

Antioxidant activity of thiocholesterol on copper-induced oxidation of low-density lipoprotein.

The effect of thiocholesterol (SH-Chol) on the copper-induced in vitro oxidation of low-density lipoprotein (LDL; 1.019 < d < 1.063) was investigated. Among the antioxidants tested, including cysteine, glutathione, 2-mercaptoethanol, dithiothreitol, probucol, thiopalmitic acid, and SH-Chol, SH-Chol was the most effective antioxidant in copper-induced LDL oxidation. Also, SH-Chol completely inhibited the formation of oxysterols, i.e., 7-hydroxycholesterol and 7-ketocholesterol, in LDL particles and reduced 1,1-diphenyl-2-picrylhydrazyl used as stable free-radical model. Moreover, SH-Chol suppressed the degradation of endogenous alpha-tocopherol in LDL particles. These findings indicate that SH-Chol acts as antioxidant in the oxidative damage of LDL in vitro and as a free-radical scavenger in lipid peroxidation.

Antioxidants↗

PubMed1991

Unusual product ratios resulting from the gamma-irradiation of cholesterol in liposomes.

Cholesterol in aqueous suspensions of multilamellar vesicles (MLV) was exposed to gamma-irradiation (0.5-10 kGy) at 0-4 degrees C. Cholesterol oxidation products resulting from the irradiation were isolated by dry column extraction followed by preparative thin-layer chromatography (TLC) and were quantitated by on-column gas chromatography (GC). The ratio of 7-ketocholesterol/cholesterol 5,6-epoxides generated by irradiation was less than one, much lower than the ratio of ten commonly produced by autoxidation. Irradiation also produced relatively higher amounts of 7-hydroxycholesterol than did autoxidation. These unique product ratios may be suitable indicators of past exposure to irradiation.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1983

Altered sterol synthesis and its relationship to fluid-phase endocytosis in a macrophage cell line P388D1.

In a previous study glucocorticoids have been shown to depress the rate of fluid-phase endocytosis in a macrophage cell line, P388D1. This effect was observed when either fluorescein-labeled dextran or horseradish peroxidase (HRP) was used to measure endocytosis. In this report the relationship between cholesterol synthesis and endocytosis was examined in light of the ability of glucocorticoids to inhibit cholesterol biosynthesis. Two known inhibitors of cholesterol biosynthesis, ML-236B and 25-hydroxycholesterol (25-OH), were compared with dexamethasone (dex) for the ability to suppress endocytosis in cells grown in media supplemented with either 10% whole or delipidized neonatal bovine serum (NBS). In 10% whole serum all inhibitors reduced the uptake of HRP after 12 h incubation. Dexamethasone (1 microM) suppressed endocytosis by 30% whereas 25-OH (2.5 microM) and ML-236B (11.6 microM) inhibited by 38 and 52%, respectively. Supplementation of the growth medium with mevalonolactone (3.4 mM) prevented the inhibition of endocytosis by ML-236B. In contrast, mevalonolactone supplementation did not prevent either dex or 25-OH from suppressing endocytosis. The same pattern of results was obtained when cultures were grown in delipidized NBS. After 4 h all inhibitors caused a decrease in amount of [14C]acetate incorporated into both nonsaponifiable lipids and digitonin precipitable sterols. Although dex inhibited cholesterol biosynthesis, total cellular cholesterol was unaffected by dex treatment after 24 h incubation. It is suggested that in addition to suppressing mevalonate synthesis, 25-OH, and by analogy dex, may act at some metabolic site(s) distal to the formation of mevalonate.

Animals↗

PubMed2006

Liver X receptor agonists ameliorate TNFalpha-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression.

AIMS/HYPOTHESIS: The nuclear receptors, including nuclear receptor subfamily 1, group H, member 3 (NR1HR, also known as liver X receptor [LXR]), are sensors of cholesterol metabolism and lipid biosynthesis that have recently been proposed as insulin sensitisers. TNFalpha has been described as a link between obesity and the development of insulin resistance, an important contributor to the pathogenesis of type 2 diabetes. Therefore, we decided to investigate the ability of NR1HR agonists to ameliorate TNFalpha-induced insulin resistance in brown adipocytes. METHODS: Primary brown adipocytes from rat fetuses, and from wild-type neonate mice and neonate mice deficient in the gene encoding protein tyrosine phosphatase-1B (Ptpn1, also known as Ptp1b) were cultured in the absence or presence of TNFalpha and different nuclear receptor agonists. Among them, the unrelated NR1HR ligands T0901317, GW3965 and (22R)-hydroxycholesterol were tested. After insulin stimulation, glucose uptake and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) translocation were measured. Next the insulin signalling cascade was determined by submitting cells to lysis, immunoprecipitation and immunoblotting. RESULTS: NR1HR agonists ameliorate TNFalpha-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane. This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/phosphatidylinositol 3-kinase/protein kinase B, and could be due to the fact that T0901317 prevents the increase of PTPN1 production and phosphatase activity produced by TNFalpha. In this regard, Ptpn1-deficient brown adipocytes showed protection against insulin resistance by TNFalpha. Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase zeta and/or the increase of Slc2a4 expression. CONCLUSIONS/INTERPRETATION: Nuclear receptors NR1HR are interesting potential targets for drug treatment of insulin resistance.

Adipocytes↗

PubMed2003

Consecutive administration of paraquat to rats induces enhanced cholesterol peroxidation and lung injury.

It is our hypothesis that as a consequence of increased oxidative stress, rats develop lung injury with increased cholesterol-derived hydroperoxides and oxysterols in lung after consecutive exposure of the rats to paraquat. To test this we administered 10 mg/kg of paraquat i.p. once or seven times (once a day) to Wistar rats. Rats were killed, and lung tissue was collected 24 h after the last paraquat injection. We found that in response to consecutive paraquat doses, there were significant increases in 7alpha- and 7beta-hydroperoxycholest-5-en-3beta-ol (7alpha-OOH and 7beta-OOH; P=0.01) as well as 7alpha- and 7beta-hydroxycholesterol (7alpha-OH and 7beta-OH; P=0.01), and 7-ketocholesterol (7-keto; P=0.03). In addition, pulmonary hemorrhage, thickening of alveolar septum, and inflammatory cell infiltration of macrophages were observed. This is the first report showing enhanced cholesterol peroxidation and lung injury of rats due to consecutive doses of paraquat.

Animals↗

PubMed2026

Identifying potential drug targets for physical and cognitive frailty: an integrative analysis of CHARLS cohort, mendelian randomization, and gene colocalization.

With the aging of the population, frailty has become a common syndrome that severely affects the quality of life of older adults. This study aims to analyze the correlation between cognition and frailty, physical activity and frailty, and elucidate the potential pharmacological targets of cognitive frailty and physical frailty.We conducted logistic regression analyses using data from the China Health and Retirement Longitudinal Study (CHARLS) to examine the associations between total cognition and frailty, physical activity and frailty. Furthermore, summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (TSMR) were employed to explore potential pharmacological targets for frailty. Genes associated with physical frailty and cognitive frailty were identified, followed by analysis via colocalization analysis, phenome-wide association studies (PheWAS), and DsigDB drug prediction. Cross-sectional analysis of CHARLs revealed that total cognition(OR 0.93, 95% CI 0.92-0.95) and middle physical activity(OR 0.95, 95% CI 0.92-0.97) were negatively correlated with frailty. SMR identified 41 drug genes associated with frailty, and subsequent TSMR validation and co-localization analysis showed that 11 candidate genes exhibited strong colocalization (PP.H4 > 0.8). GRPEL 1, PABPC 4, and WBP 2NL were ultimately identified as potential drug targets associated with physical frailty, while LANCL1, LRPPRC, FADS1, and WBP2NL were identified as potential drug targets associated with cognitive frailty. Phenome-wide association analysis(PheWAS) did not reveal any significant associations between these genes and other phenotypes at the genome-wide significance threshold. Laudanosine, 25-hydroxycholesterol, and hexadecanal emerged as the top three candidate compounds for therapeutic intervention. We identified potential drug targets for physical frailty and cognitive frailty through comprehensive analysis and elucidated drugs associated with potentially relevant genetic markers, thereby laying the foundation for a deeper understanding of the mechanisms of frailty.

Humans↗

PubMed2000

Structure-apoptotic potency evaluations of novel sterols using human leukemic cells.

Three oxidized analogs of cholesterol have been characterized for their ability to cause apoptotic cell death in CEM-C7-14 human leukemic cells. In addition to testing 15-ketocholestenol (K15), 15-ketocholestenol hydroxyethyl ether (CK15), and 7-ketocholesterol hydroxyethyl ether (CK7), an oxysterol of known apoptotic response, 25-hydroxycholesterol (25OHC), served as a standard for comparison. Growth studies based on dye exclusion by viable cells while using a sublethal concentration of oxysterols ranked their potency for cell kill as 25OHC > K15 > CK15 > CK7. Both the TUNEL assay (terminal deoxynucleotidyl transferase-mediated dUTP-X nick end labeling), which quantifies the amount of DNA nicks caused by a toxic agent, and the MTT assay, which measures cell metabolism and thus reflects cell viability, substantiated the same rank order. An ELISA assay for evaluating release of DNA fragments into the cytosol after treatment gave a similar potency order. The oncogene c-myc mRNA was suppressed by all three oxysterols, with 25OHC and K15 being the most potent suppressors. Hoechst and Annexin V staining documented that these oxysterols kill cells by an apoptotic pathway as evidenced by condensation of nuclear chromatin and plasma membrane inversion, respectively. From these in vitro studies, we believe that 25OHC, K15, and possibly CK15 have the potential to be chemotherapeutic agents.

Apoptosis↗

PubMed2000

Plasma oxysterols and tocopherol in patients with diabetes mellitus and hyperlipidemia.

The plasma levels of free oxysterols (7-ketocholesterol; 7alpha-hydroxy-, 7beta-hydroxy-, 25-hydroxy-, and 27-hydroxycholesterol; and 5alpha,6alpha-epoxycholestanol) in patients with diabetes mellitus and hypercholesterolemia were determined using gas chromatography-mass spectrometry with selective ion monitoring. We studied 39 patients with diabetes mellitus, 20 nondiabetic patients with hypercholesterolemia, and 37 normal controls. Plasma cholesterol levels in diabetic and hypercholesterolemic patients showed no statistical difference. Plasma 7-ketocholesterol was significantly higher in patients with diabetes (31.6+/-2.8 ng/mL) or hypercholesterolemia (52.3+/-5.9) than in the control group (22.4+/-1.2). The increased plasma cholesterol can be regarded as an oxidation substrate for the oxidant stress and the higher absolute levels of oxysterols in hypercholesterolemic plasma compared with the control plasma. This difference disappeared when 7-ketocholesterol was expressed in proportion to total cholesterol. The oxidizability of plasma cholesterol was evaluated by comparing the increased ratio of 7-ketocholesterol after CuSO4 oxidation to the ratio before. We demonstrated that the patients with diabetes showed increased oxidizability (77.5%) compared with the control (36.6%) or hyperlipemic group (45.3%), which is likely due to the lower amounts of alpha-tocopherol in the diabetics. Measurement of oxysterols may serve as a marker for in vivo oxidized lipoproteins in diabetes and hyperlipemia.

Cholesterol↗

PubMed2002

Selective effect of cholesterylphosphoserine on intracellular cholesterol transport.

Cholesteryl-3beta-phosphoserine (CPHS) is a synthetic steroid affecting intracellular cholesterol transport. To compare CPHS with the well-known inhibitors progesterone and U18666A, we examined cholesterol transport in three human cell lines: the monocytic U-937, the endothelial ECV-304, and the lymphoid Jurkat. Under low density lipoprotein (LDL) loading, CPHS inhibited cholesterol esterification in U-937 and ECV-304 cells but not in Jurkat cells. In contrast, CPHS inhibited the mobilization of plasma membrane cholesterol induced by 25-hydroxycholesterol, brefeldin A, or sphingomyelinase in all cell lines. In cells pulse-labeled with [3 H]cholesterol, CPHS decreased incorporation of cholesterol and inhibited its esterification. In prelabeled cells, CPHS promoted cholesterol efflux and enhanced the cyclodextrin-mediated removal of plasma membrane cholesterol. CPHS did not affect endogenous cholesterol synthesis nor acylcoenzyme A:cholesterol acyltransferase activity. These data suggest that, unlike progesterone and U18666A, CPHS inhibits intracellular cholesterol transport by specifically affecting the movements of cholesterol in the plasma membrane. Owing to this restricted site of action, CPHS may help to clarify the role of the plasma membrane in cholesterol trafficking. For example, the lack of an effect of CPHS on the esterification of LDL-derived cholesterol in Jurkat cells suggests that most of the LDL-derived cholesterol in these cells is directly delivered to the endoplasmic reticulum without cycling through the plasma membrane.

Androstenes↗

PubMed2002

Simultaneous evaluation of HMG-CoA reductase and cholesterol 7alpha-hydroxylase activities by electrospray tandem MS.

Simultaneous evaluation of HMG-CoA reductase and cholesterol 7alpha-hydroxylase activities by electrospray tandem mass spectrometry (ES-MS-MS) was performed. The assay was based on the measurement of mevalonolactone (MVL) and 7alpha-hydroxycholesterol (7alpha-OHC) produced by the incubation of HMG-CoA with hepatic microsomes in the presence of NADPH and glucose-6-phosphate dehydrogenase. Following extraction and purification using a cyanopropyl cartridge, MVL and 7alpha-OHC were analyzed, without derivatization, by ES-MS-MS. The analysis was achieved in 5 min. Calibration curves were made for MVL and 7alpha-OHC, and were linear from 0 to 100 microg. The recovery was >97%. The procedure was validated under similar calibration and recovery experiments, by measuring the above mentioned products as dimethylethylsilyl ether derivatives using the classical technique of GC-MS. Data obtained by ES-MS-MS and GC-MS showed a good correlation, with no significant differences. ES-MS-MS is a simple and reliable method for the evaluation of HMG-CoA reductase and cholesterol 7alpha-hydroxylase activities in liver microsomal preparations.

Animals↗

PubMed1983

The use of amphotericin B to detect inhibitors of cellular cholesterol biosynthesis.

Pores formed in the membranes of animal cells by complexes of sterols and the polyene antibiotic amphotericin B can efficiently kill the cells. Thus, in the absence of exogenous sources of cholesterol, inhibitors of enzymes in the cholesterol biosynthetic pathway render cells resistant to amphotericin B. Preincubation of Chinese hamster ovary cells with compactin or 25-hydroxycholesterol, inhibitors of the synthesis of the key intermediate mevalonate, protected cells from amphotericin B killing and this protection was reversed by the addition of exogenous mevalonate. The ability of compactin to confer amphotericin B resistance on normal cells was abolished when cells were provided exogenous cholesterol by the receptor-mediated endocytosis of low density lipoprotein. Low density lipoprotein receptor-defective Chinese hamster ovary cells were not subject to this low density lipoprotein-dependent amphotericin B killing. Exogenous mevalonate did not prevent 4,4,10 beta-trimethyl-trans-decal-3 beta-ol, an inhibitor of mevalonate conversion to sterols, from protecting cells from amphotericin B. A simple two-step protocol in which cells are preincubated (15-24 h) with potential inhibitors and then treated (3-6 h) with amphotericin B was devised to provide a sensitive method for detecting direct (e.g., competitive) and regulatory inhibitors of cholesterol biosynthesis. This protocol may prove useful in detecting potential antihypercholesterolemia drugs and is currently being used to isolate mutants in receptor-mediated endocytosis.

Acyl Coenzyme A↗

PubMed1985

Capillary column gas-liquid chromatographic resolution of oxidized cholesterol derivatives.

Fused-silica capillary columns were evaluated for the resolution of oxidized cholesterol derivatives. Thermal instability of diol derivatives, epimeric 7 alpha- and 7 beta-hydroxy, 4 beta-hydroxy, and 25-hydroxycholesterol, was observed during gas chromatography. After derivatization as trimethylsilyl ethers the foregoing diols, alpha-epoxide, cholestane-triol, 7-ketocholesterol, and cholesta-3,5-dien-7-one were completely resolved on a DB-1 column. Each oxidized sterol revealed excellent response linearity as the trimethylsilylated sterol, enabling reliable quantification. The identity of each derivatized sterol was confirmed by mass spectrometry.

Cholesterol↗

PubMed1986

An improved method for assay of cholesterol 7 alpha-hydroxylase activity.

An improved assay method for cholesterol 7 alpha-hydroxylase which is accurate, sensitive, and yet still simple is described. The method consists of two parts: the first part is cholesterol 7 alpha-hydroxylation in liver microsomes utilizing cholesterol in situ as the substrate, and the second part is conversion of the product, 7 alpha-hydroxycholesterol, into 7 alpha-hydroxy-4-cholesten-3-one having an intense absorption at 240 nm by the action of cholesterol oxidase. The converted sterol is then analyzed by high-performance liquid chromatography. During the second enzyme reaction, the first enzyme reaction is halted and further metabolism of the product is prevented. In consequence, the method had more than 10-fold increase in the sensitivity than the previous one.

Animals↗

PubMed1989

Simultaneous measurement of cholesterol 7 alpha-hydroxylase activity by reverse-phase high-performance liquid chromatography using both endogenous and exogenous [4-14C]cholesterol as substrate.

The HPLC-spectrophotometric method (T. Ogishima and K. Okuda (1986) Anal. Biochem. 158, 228-232) for measuring cholesterol 7 alpha-hydroxylase activity was modified by using a C-18 reverse-phase column to separate 7 alpha-hydroxy-4-cholesten-3-one and 4-cholesten-3-one and by adding 7 beta-hydroxycholesterol to each reaction mixture as an internal recovery standard. With this method, we were able to simultaneously measure cholesterol 7 alpha-hydroxylase activity using endogenous cholesterol and exogenous [4-14C]cholesterol as substrate. Rat liver cytosol differentially stimulated (286%) the 7 alpha-hydroxylation of exogenous [4-14C]-cholesterol. In contrast, total cholesterol 7 alpha-hydroxylase activity was stimulated only 35% by cytosol. This method should prove useful for studying mechanisms of cholesterol delivery to cholesterol 7 alpha-hydroxylase.

Animals↗

PubMed1990

Heterogeneous pools of cholesterol side-chain cleavage activity in adrenal mitochondria from adrenocorticotropic hormone-treated rats: reconstitution of the isocitrate response with succinate and low concentrations of isocitrate.

Cholesterol side-chain cleavage in isolated adrenal mitochondria requires unique energy requirements that may determine not only electron transport to P450 but also cholesterol availability. In mitochondria from ACTH-treated rats, two approximately equal pools of reactive cholesterol are indicated by the partial effectiveness of succinate (SU; Type A), and the metabolism of residual cholesterol by 1 mM isocitrate (IC; Type B). Type A metabolism is associated with relatively few initial cholesterol-P450scc complexes and is rapidly and selectively lost when mitochondria are preincubated without an energy source. We now show that cholesterol metabolism supported by IC resolves into equal high and low affinity components (EC50 = 10 and 250 microM) exhibiting, respectively, Type A and Type B characteristics. SU and 50 microM IC, in combination, provided nearly the same activity characteristics as 1 mM IC, including resistance to preincubation and increased turnover of cholesterol-P450scc complexes. Much higher (three to six times) and more sustained pregnenolone formation was seen, with all reductants, following either enhancement of the reactive cholesterol pool or addition of 20-alpha-hydroxycholesterol, indicating that adrenocorticotropic hormone-mitochondria are limited by substrate availability. ATP generation was most effectively supported by SU, and IC was maximally active at 50 microM, emphasizing differences between respiratory and steroidogenic energy requirements. ATP production and the maintenance of uniform suppression after in vivo cycloheximide treatment indicate the integrity of the mitochondrial interaction with all reductants. Inhibitors of SU oxidation (KCN, malonate) strongly inhibited SU-supported cholesterol metabolism but had little effect on SU synergism with IC. Fumarate (but not alpha-ketoglutarate or oxaloacetate) was equally effective as a synergist, but was totally ineffective as a reductant. SU or fumarate, therefore, act by a nonreductive pathway to boost NADPH production from low concentrations of IC. This decrease in apparent Km for IC may be mediated by stimulation of mitochondrial uptake of the reductant through the specific transporters.

Adrenal Glands↗