Disease relevance of sulfaphenazole

• Among these inhibitors, sulfaphenazole and phalloidin were able to reduce hU-II-induced hypotension [1].
• Rat hearts were perfused in the Langendorff mode for 20 min in the presence, or absence, of sulfaphenazole and then subjected to 30 min global no-flow ischemia followed by 15 min reperfusion [2].
• Aerosol gene transfer of recombinant adenovirus containing the human CYP2C9 significantly elevated mean pulmonary artery pressure and total pulmonary resistance indices, both of which were sensitive to the inhibitor sulfaphenazole [3].

High impact information on sulfaphenazole

• The specific CYP 2C9 inhibitor, sulfaphenazole, prevented both the enhanced cell proliferation and up-regulation of cyclin D1 [4].
• The specific CYP2C9 inhibitor sulfaphenazole, on the other hand, significantly attenuated EDHF-mediated hyperpolarization and relaxation [5].
• The rate of elimination of tolbutamide was decreased within 1 to 2 hr of a single dose of sulfaphenazole and the tolbutamide half-life was increased from 9.2 hr to 25.7 hr (n = 2) [6].
• Tolbutamide half-life was increased by chronic administration of sulfaphenazole (9.5 hr to 28.6 hr, n = 2), phenylbutazone (7.9 hr to 23.1 hr, n = 8), and oxyphenbutazone (8.1 hr to 30.2 hr, n = 2) [6].
• The inhibitory effects of a series of sulfaphenazole (SPA) derivatives were studied on two modified forms of rabbit liver cytochrome P450 2C5 (CYP2C5), CYP2C5dH, and structurally characterized CYP2C5/3LVdH and compared to the previously described effects of these compounds on human CYP2C8, 2C9, 2C18, and 2C19 [7].

Biological context of sulfaphenazole

• Although they differ at only 43 of 490 amino acids, sulfaphenazole (SFZ) is a potent and selective inhibitor of P450 2C9 with an IC50 and a spectrally determined binding constant, KS, of <1 microM [8].
• Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes [9].
• These enzymes showed similarities in kinetics of phenytoin hydroxylation and sulphaphenazole inhibition compared with human liver phenytoin hydroxylase [10].
• By means of purification, N-terminal amino acid sequencing and inhibition by antibodies and sulfaphenazole, we have identified the form of cytochrome P450 primarily responsible for 58C80 hydroxylation in human liver, P450hB20-27, to be a member of the P450 2C9 subfamily [11].
• After pretreatment with L-NMMA (16 micromol/min) and ibuprofen (1200 mg, orally), sulphaphenazole (6 mg/min) did not substantially inhibit bradykinin-induced vasodilation [12].

Anatomical context of sulfaphenazole

• METHODS: In vitro kinetic and inhibition studies were performed in human liver microsomes using prototypic probe substrates of CYP2C9 and CYP2D6, with various inhibitors (miconazole, sulfaphenazole, fluconazole, ketoconazole, quinidine, fluoxetine, fluvoxamine) [13].
• Sulfaphenazole potently inhibited 3alpha-hydroxydesogestrel formation by CYP2C9 microsomes with a Ki value of 0.91 microM [14].
• The cytochrome P450 (CYP) 2C9 inhibitor sulphaphenazole was recently identified as a potent inhibitor of NO- and prostacyclin (PGI2)-independent relaxation in porcine coronary arteries [12].
• In rabbits, the Kp values of six tissues studied (i.e., brain, heart, spleen, small intestine, muscle, and skin) increased in the presence of sulfaphenazole ; except for brain, lung, and adipose tissue, the tissue-to-plasma unbound concentration ratio (Kp,f) of other tissues did show a significant decrease [15].
• METHODS: The authors examined myogenic responses of mesenteric arteries isolated from control and CH (48 h; P(B) = 380 mmHg) rats in the presence of a HO inhibitor (zinc protoporphyrin IX; ZnPPIX) or combined HO and CYP epoxygenase inhibition (sulfaphenazole) [16].

Associations of sulfaphenazole with other chemical compounds

• On the contrary, sulfaphenazole led to a low-spin (S = 1/2) CYP 2C9 complex upon binding of its NH2 group to CYP 2C9 iron [17].
• However, furafylline (CYP1A inhibitor), tolbutamide (CYP2C substrate), and sulfaphenazole (CYP2C inhibitor) were essentially noninhibitory [18].
• In the absence of oxygen, tolbutamide, diclofenac, warfarin and sulfaphenazole did not alter the redox potential of the iron heme [19].
• We further compared Michaelis-Menten and sulfaphenazole inhibition constants for (S)-warfarin 7-hydroxylation catalyzed by cDNA-expressed 2C9 and by human liver microsomes [20].
• We observed the inhibition of (R)- and (S)-flurbiprofen 4'-hydroxylation by an inhibitor of P450 2C9, sulfaphenazole (Ki = 0.07 and 0.06 microM, respectively), and the NSAID piroxicam (Ki = 10 and 7 microM, respectively) [21].

Gene context of sulfaphenazole

• In addition, when sulfaphenazole was combined with S-mephenytoin, further inhibition of 3alpha-hydroxydesogestrel formation was observed suggesting a possible role for CYP2C19 [14].
• Sulfaphenazole, flavoxamine, and antibodies raised against purified liver cytochrome P450 (P450) 2C9 that inhibit both CYP2C9- and 2C19-dependent activities, significantly inhibited microsomal oxidations of (+)- and (-)-limonene enantiomers [22].
• The addition of quinidine, a selective inhibitor of CYP2D6, along with triacetyloleandomycin and sulphaphenazole produced an additional decrease in the rate of NT formation in all but the PM liver, but did not completely eliminate the reaction [23].
• This assumption was confirmed by inhibition with ketoconazole and ritonavir (two potent inhibitors of CYP3A) whereas sulfaphenazole (2C9 inhibitor) and quinidine (2D6 inhibitor) were inefficient [24].
• Predictions from kinetic studies on heterologously expressed CYPs are consistent with chemical inhibition studies on human liver microsomes with sulfaphenazole and alpha-naphthoflavone that suggest a greater role for CYP2C9, and a smaller role for CYP1A2, at higher substrate concentrations [25].

Analytical, diagnostic and therapeutic context of sulfaphenazole

• Effect of pH and small inorganic ions on binding of sulfadimethoxine and sulfaphenazole to human serum albumin measured by circular dichroism [26].
• METHODS: In 36 healthy subjects (normotensive [NT]) and 32 hypertensive patients (HT), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intraarterial acetylcholine (ACH) and bradykinin (BDK), repeated during N(G)-monomethyl-L-arginine (L-NMMA) (100 mug/100 ml/min) or SUL (0.03 mg/100 ml/min) [27].

References