Microsomes, oxidation

Since the results of our experiments with isolated rat liver fractions supported a reaction sequence Initiated by microsomal oxidation of the nitrosamine leading to formation of a carbonium ion, the results of the animal experiment suggested that in the intact hepatocyte, one of the earlier electrophilic intermediates (II, III or V, Figure 1) is intercepted by nucleophilic sites in DNA (exemplified here by the N7 position of guanine) before a carbocation is formed. 

Further experiments on the metabolism of NDPA by rat liver fractions have also provided support for the 3-oxidation mechanism of Kruger. In addition to the products of a-oxidation, we have isolated and characterized NHPPA as a major product of the microsomal oxidation of NDPA (18). We have also shown that NHPPA is further oxidized to NOPPA by microsomal preparations from rat liver (18), Finally, with NOPPA as substrate, we have shown that metabolism takes place principally by reduction with the microsomal or soluble fraction of rat liver to yield NHPPA, although microsomal a-oxidation also takes place to some extent (19). 

Klein, S.M., Cohen, G., Lieber, C.S. and Cederbaum, A.l. (1983). Increased microsomal oxidation of hydroxyl scavenging agents and ethanol after chronic consumption of ethanol. Arch. Biochem. Biophys. 223, 425-432. 

Iron complexes or microsomal nonheme iron are undoubtedly obligatory components in the microsomal oxidation of many organic compounds mediated by hydroxyl radicals. In 1980, Cohen and Cederbaum [27] suggested that rat liver microsomes oxidized ethanol, methional, 2-keto-4-thiomethylbutyric acid, and dimethylsulfoxide via hydrogen atom abstraction by hydroxyl radicals. Then, Ingelman-Sundberg and Ekstrom [28] assumed that the hydroxylation of aniline by reconstituted microsomal cytochrome P-450 system is mediated by hydroxyl radicals formed in the superoxide-driven Fenton reaction. Similar conclusion has been made for the explanation of inhibitory effects of pyrazole and 4-methylpyrazole on the microsomal oxidation of ethanol and DMSO [29],... 

On the other hand, microsomes may also directly oxidize or reduce various substrates. As already mentioned, microsomal oxidation of carbon tetrachloride results in the formation of trichloromethyl free radical and the initiation of lipid peroxidation. The effect of carbon tetrachloride on microsomes has been widely studied in connection with its cytotoxic activity in humans and animals. It has been shown that CCI4 is reduced by cytochrome P-450. For example, by the use of spin-trapping technique, Albani et al. [38] demonstrated the formation of the CCI3 radical in rat liver microsomal fractions and in vivo in rats. McCay et al. [39] found that carbon tetrachloride metabolism to CC13 by rat liver accompanied by the formation of lipid dienyl and lipid peroxydienyl radicals. The incubation of carbon tetrachloride with liver cells resulted in the formation of the C02 free radical (identified as the PBN-CO2 radical spin adduct) in addition to trichoromethyl radical [40]. It was found that glutathione rather than dioxygen is needed for the formation of this additional free radical. The formation of trichloromethyl radical caused the inactivation of hepatic microsomal calcium pump [41]. 

Microsomal oxidation of amines and phenols may proceed by different ways. For example, it has been shown [42] that phentermine (2-methyl-l-phenyl-2-propylamine) is hydro-xylated to /V-hydroxyphcntcrminc by rat liver cytochrome P-450 system through a normal cytochrome P-450 way ... 

The constituent of paint, 2-nitropropane, exhibiting genotoxicity and hepatocarcinogeni-city was oxidized by liver microsomes forming nitric oxide, which was identified as a ferrous NO complex [61]. Clement et al. [62] concluded that superoxide may participate in the microsomal oxidation of /Y-hydroxyguanidincs, which produced nitric oxide, urea, and the cyanamide derivative. Caro et al. [63] suggested that the oxidation of ketoxime acetoxime to nitric oxide by microsomes enriched with P-450 isoforms might be mediated by hydroxyl or hydroxyl-like radicals. 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by microsomal oxidation followed by glucuronide conjugation. 

Mansuy, D., Beaune, P., Crestell, T., Lange, M., and Leroux, M. 1977. Evidence for phosgene formation during liver microsomal oxidation of chloroform. Biochem. Biophys. Res. Comm. 79 513-517. 

Surbrook, S.E., and M.J.Olson. 1992. Dominant role of cytochrome P-450 2E1 in human hepatic microsomal oxidation of the CFC-substitute 1,1,1,2-tetrafluoroethane. Drug Metab. Dispos. 20 518-524. 

Tynes RE, Hodgson E. 1985. Magnitude of involvement of the mammalian flavin-containing monooxygenase in the microsomal oxidation of pesticides. J Agric Food Chem 33 471-479. 

The liver alcohol dehydrogenase mentioned in the preceding section has the same pro-R stereospecificity for NAD and ethanol as yeast alcohol dehydrogenase. Furthermore, the oxidation of ethanol by a microsomal oxidizing system, or by catalase and H2O2, likewise proceeds with pro-R stereospecificity for the ethanol77>. The catalase-H2C>2 system is so very different, however, from the pyridine nucleotide dehydrogenase, that one wonders whether the similarity in stereospecificity for ethanol is fortuitous. 

M. Isobe, T. Sone, E. Takabatake, An Unstable Epoxy Intermediate Formed by the Microsomal Oxidation of 4-Nitrophenyl Vinyl Ether , Chem. Pharm. Bull. 1988, 36, 2267 -2269. 

Evidence from animal bioassays supports the hypothesis that it is the cytosolic system and not the microsomal oxidative system that is responsible for the carcinogenicity of 1,2-dibromoethane. 

Microsomal oxidations may be subdivided into aromatic hydroxylation aliphatic hydroxylation alicyclic hydroxylation heterocyclic hydroxylation N-, S-, and O-dealkylation N-oxidation N-hydroxylation S-oxidation desulfuration deamination and dehalogenation. 

Non-microsomal oxidations may be subdivided into amine oxidation, alcohol and aldehyde oxidation, dehalogenation, purine oxidation, and aromatization. 

Sharer, J.E., Duescher, R.J. Elfarra, A.A. (1992) Species and tissue differences in the microsomal oxidation of 1,3-butadiene and glutathione conjugation of butadiene monoxide in mice and rats. Drug Metah. Disp., 20, 658-664... 

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