Cytochrome P-450 inhibitor

Other compounds of this general class which have been found to have antiestrogenic properties include the cytochrome P-450 inhibitor, SKF 525A P02-33-0](Sl) (24) JV, JV-diethyl-2-[(4-phenylmethyl)phenoxy]ethanamine [98774-23-3] (DPPE)(58) (42) /-Butylphenoxyethyl diethylamine [57586-10-4] (BPEA)(59) (43) and cyclofenil [110042-18-7] (60, R = C H ) (24) analogues. 

Saito et al. (134) found that the cytosolic nitroreductase activity was due to DT-diaphorase, aldehyde oxidase, xanthine oxidase plus other unidentified nitroreductases. As anticipated, the microsomal reduction of 1-nitropyrene was inhibited by 0 and stimulated by FMN which was attributed to this cofactor acting as an electron shuttle between NADPH-cytochrome P-450 reductase and cytochrome P-450. Carbon monoxide and type II cytochrome P-450 inhibitors decreased the rate of nitroreduction which was consistent with the involvement of cytochrome P-450. Induction of cytochromes P-450 increased rates of 1-aminopyrene formation and nitroreduction was demonstrated in a reconstituted cytochrome P-450 system, with isozyme P-448-IId catalyzing the reduction most efficiently. 

Cytochrome P-450 systems are also present in both smooth muscle [54, 5 5] and endothelial [56] cells. In studies of hepatic [57] and aortic [58] microsomes, Bennett and colleagues showed that bioconversion of GTN to GDN was NADPH dependent and was inhibited by the cytochrome P-450 inhibitor, SKF 525A. In hepatic microsomes, moreover, conversion of GTN led to activation of sGC [59]. 

Use of piperonyl butoxide, a potent cytochrome P-450 inhibitor, has been recommended as an effective means for preventing the degradation of chloramphenicol. Since addition of this substance to liver homogenates could result in a recovery enhancement from about 30% to 60%, it was suggested that incurred tissue samples taken for analysis should be frozen immediately after excision and homogenized in water containing 2.5% piperonyl butoxide (11). 

Another class of cytochrome P-450 inhibitors, compounds with a monosubstituted acetylenic function, are well known for their potential as insecticide synergists (21) and some have already been reported to be active as JH biosynthesis inhibitors as well (19, 22). Ortiz de Montellano and Kunze (23) have shown that many ethynyl substrates cause the destruction of rat hepatic cytochrome P-450, when the prosthetic heme is alkylated during attempted metabolism of the triple bond. Such suicide substrates must bind to the enzyme and be catalytically acceptable thereby offering a potential for selectivity. In fact, selectivity of suicide substrates for particular molecular forms (isozymes) of hepatic... 

The renal cytochrome P-450 enzyme system is involved in oxidative reactions in which an atom of molecular oxygen is inserted in an organic molecule. The flavoprotein NADPH-cytochrome P-450 reductase is an essential component of the mixed-function oxidase systems (MFO). Microsomal membranes appear to be particularly subject to attack by reactive oxygen radicals due to their high content of unsaturated fatty acids and the presence of the cytochrome P-450 system [40]. Cephaloridine-induced peroxidation of membrane lipids is decreased by the cytochrome P-450 inhibitor cobalt chloride [31], suggesting a role for a cytochrome P-450 reductase in the P-lactam-induced generation of reactive oxygen species and subsequent peroxidation products. 

Unlike more potent chlorinated alkanes such as carbon tetrachloride or 1,1,2-trichloroethane, it is not clear whether the hepatotoxicity of 1,1,1 -trichloroethane is due to a metabolite or the parent compound (see Section 2.3.5.). If metabolites produced by cytochrome P-450 oxidation or dechlorination are responsible for the hepatotoxicity, administering cytochrome P-450 inhibitors (e.g., SKF-525A) may inhibit the development of toxic effects on the liver. Clinical or animal studies examining the use of such an approach and the possibility of side effects, however, were not located. 

A-demethylation of 1,1-dimethylhydrazine by rat and hamster liver microsomes in vitro required the presence of NADPH and oxygen and was decreased by the addition of flavin-containing monooxygenase inhibitor (methimazole) but not by the addition of cytochrome P-450 inhibitors (Prough et al. 1981). 

Pai, K.S. and Ravindranath, V. (1991) Protection and potentiation of MPTP-induced toxicity by cytochrome P-450 inhibitors and inducer in vitro studies with brain slices. Brain Res. 555 239-244. 

Z. Sui, and R.J. Roman (1994). Cytochrome P-450 inhibitors alter afferent arteriolar responses to elevations in pressure. Am. J. Physiol. 266, H1879-H1885. 

In addition, it can be inhibited by specific cytochrome P-450 inhibitors (Table 2). 

An enzyme from the flowers of Sinningia cardinalis Reichsteinia cardinalis, Gesneriaceae) has hydrolase activity associated with microsomal fractions and requires NADPH as an essential cofactor (hydrolyase activity II). This enzyme converts naringenin (10) and apigenin (5) to eriodictyol (17) and luteolin (4), respectively (Dewick, 1989). The flavone synthase activity of this enzyme was abolished completely by treatment with the cytochrome P-450 inhibitor ancymidol, but the flavonoid 3 -monooxygen-ase activity was not altered. 

Azoreductase activity (substrate l,2-dimethyl-4-(/ -carboxyphenylazo)-5-hydroxybenzene (CPA) (Hanzel and Carlson 1974) and nitroreductase activity (substrate. 77-nitrobenzoic acid) (Carlson 1972) have been detected in digestive gland of M. mercenaria (Table 12). Their properties were similar to those of mammalian enzyme activities and considered indicative of the existence of two separate enzyme systems. Nitroreductase activity was maximal at 35 to 45 C and pH 6.0, Stimulated by flavin mononucleotide, and inhibited by potassium cyanide and air, but not by SKF-525A or carbon monoxide (cytochrome P-450 inhibitors). Azoreductase activity was similarly stimulated by flavin mononucleotide and inhibited by air, but had a pH optimum of 8.0 activity was higher at 37 C than at 22 °C. Both enzyme activities had cytosolic and microsomal subcellular localizations, viz. activity in nmol min g wet weight (% distribution in brackets)... 

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