Microsomal mammalian

Unexpectedly, as compared with microsomal mammalian epoxide hydrolases, all the meso-epoxides tested with the two above mentioned bacterial enzymes were not substrates. 

Pyrethroids from Chiysanthemic Acid. The unsaturated side chains of the aHethrolone alcohol moieties of the natural pyrethrins are readily epoxidized by microsomal oxidases and converted to diols, thus detoxifying the insecticides. Esterification of chrysanthemic acid (9), R = CH3, with substituted ben2yl alcohols produces usehil insecticides barthrin [70-43-9J, 2-chloro-3,4-methylenedioxyben2yl (+)-i7j ,/n7 j -chrysanthemate, and dimethrin [70-38-2] 2,4-dimethylben2yl (+)-i7j ,/n7 j -chrysanthemate. These have alimited spectmm of insecticidal activity but are of very low mammalian toxicity, ie, rat oralLD s >20,000 mg/kg. 

The reactivity of the individual O—P insecticides is determined by the magnitude of the electrophilic character of the phosphoms atom, the strength of the bond P—X, and the steric effects of the substituents. The electrophilic nature of the central P atom is determined by the relative positions of the shared electron pairs, between atoms bonded to phosphoms, and is a function of the relative electronegativities of the two atoms in each bond (P, 2.1 O, 3.5 S, 2.5 N, 3.0 and C, 2.5). Therefore, it is clear that in phosphate esters (P=0) the phosphoms is much more electrophilic and these are more reactive than phosphorothioate esters (P=S). The latter generally are so stable as to be relatively unreactive with AChE. They owe their biological activity to m vivo oxidation by a microsomal oxidase, a reaction that takes place in insect gut and fat body tissues and in the mammalian Hver. A typical example is the oxidation of parathion (61) to paraoxon [311-45-5] (110). 

Literature reports iadicate that sodium sorbate causes weak genotoxic effects such as chromosomal aberrations and mutations ia mammalian cells (172,173). This effect is thought to be caused by oxidative products of sodium sorbate ia stored solutions (173—175). The main oxidation product of sodium sorbate, 4,5-oxohexenoate, is mutagenic ia a Salmonella mammahan-microsome test (176). Sorbic acid and potassium sorbate were not genotoxic under the same test procedures (167,172,174—177). 

S u/woue//j/mammalian microsome assay (Ames test)... 

Lewis DFV. Qn the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics. Biochem Pharmacol 2000 60 293-306. 

Williams PA, Cosme J, Sridhar V, Johnson EF, McRee DE. Mammalian microsomal cytochrome P450 monooxygenase structural adaptations for membrane binding and functional diversity. Mol Cell 2000 5 121-31. 

Lewis DFV. Three-dimensional models of human and other mammalian microsomal P450s constructed from an alignment with P450102 (P450bm3). Xenobiotica 1995 25 333-66. 

Ames B.N., McCann J. Yamasaki E. (1975) Methods for detecting carcinogens and mutagens with the Salmonella/mammalian microsome mutagenicity test. MutatRes, 31, 347-364. 

BARTHOLOMEW R M and RYAN D s (1980) Lack of mutagenicity of some ph)doestrogens in the salmonella/mammalian microsome assay. Mutat Res. 78 (4) 317-21. 

Ciba-Geigy Ltd. 1978a. Salmonella/mammalian-microsome mutagenicity test with TK 10 509 (REOFOS 95). Experiment No. 78-2506. Ciba-Geigy Limited, Basle, Switzerland. NTIS OTS0507280. 

FMC. 1992b. Durad 550B. Salmonella/mammalian-microsome plate incorporation mutagenicity assay (Ames Test). Study No. 191-1222. FMC Corporation, Philadelphia, PA. 

Hubl, U. and Stevenson, D.E. (2001) In vitro enzymic synthesis of mammalian liver xenobiotic metabolites catalyzed by ovine liver microsomal cytochrome P450. Enzyme and Microbial Technology, 29, 306-311. 

Yusufi ANK, Cheng J, Thompson MA, Chini EN, Grande JP 2001 Nicotinic acid-adenine dinucleotide phosphate (NAADP) elicits specific microsomal Ca2+ release from mammalian cells. Biochem J 353 531—536... 

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

Scheme 42. Two pathways for the N-demethylation of cocaine by mammalian liver microsomal enzyme preparations.

Mortelmans et al. 1986 NTP 1991). Negative results were also obtained in mammalian cells, except for one observation of polyploidy in Chinese hamster CHL cells (Ishidate et al. 1984 NTP 1991 Perocco et al. 1983). Only a single report was located on the genotoxicity of 77-hexane metabolites induction of chromosome loss was observed in yeast with 2,5-hexanedione (Mayer and Goin 1994). It is also unclear if incubation with liver microsomes (S9 fraction) in in vitro genotoxicity tests results in similar metabolites to those observed in humans in vivo. 

Hamman MA, Haehner-Daniels BD, Wrighton SA, et al. Stereoselective sulfoxidation of sulin-dac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes. Biochem Pharmacol 2000 60(1) 7-17. 

Mueller, D., Nelles, J., Deparde, E. and Ami, P. (1980). The activity of S-9 liver fractions from seven species in salmonella/mammalian-microsome mutagenicity tests. Mutat. Res. 70 279-300. 

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