* * * * Dieldrin O in .NET framework

Encoding Code 128C in .NET framework * * * * Dieldrin O
* * * * Dieldrin O
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O O O Aflatoxin B1 OCH3 O Aflatoxin B1 epoxide
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Examples of aliphatic epoxidation. * denote Cl atoms.
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PHASE I REACTIONS
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OCH3
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OCH2OH
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OH +
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NO2 p -Nitroanisole
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NO2 p -Nitrophenol OH
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O C2H5O P C2H5O
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CHCl CH2CHO C Cl Cl C2H5O
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O HO P C2H5O
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Chlorfenvinphos C2H5O C2H5O
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H N CH3 HO
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HO Ethylmorphine
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Figure 7.5 Examples of dealkylation.
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rst described for the insecticide chlorfenvinphos and is known to occur with a wide variety of vinyl, phenyl, phenylvinyl, and naphthyl phosphate and thionophosphate triesters (Figure 7.5). N -dealkylation is a common reaction in the metabolism of drugs, insecticides, and other xenobiotics. The drug ethylmorphine is a useful model compound for this reaction. In this case the methyl group is oxidized to formaldehyde, which can be readily detected by the Nash reaction. S-dealkylation is believed to occur with a number of thioethers, including methylmercaptan and 6-methylthiopurine, although with newer knowledge of the speci city of the avin-containing monooxygenase (see the discussion below) it is possible that the initial attack is through sulfoxidation mediated by FMO rather than CYP.
N-Oxidation. N -oxidation can occur in a number of ways, including hydroxylamine formation, oxime formation, and N -oxide formation, although the latter is primarily dependent on the FMO enzyme. Hydroxylamine formation occurs with a number of amines such as aniline and many of its substituted derivatives. In the case of 2acetylamino uorene the product is a potent carcinogen, and thus the reaction is an activation reaction (Figure 7.6). Oximes can be formed by the N -hydroxylation of imines and primary amines. Imines have been suggested as intermediates in the formation of oximes from primary amines (Figure 7.6).
METABOLISM OF TOXICANTS
H NCOCH3 2-Acetylaminofluorene
OH NCOCH3
N-Hydroxy2-acetylaminofluorene
(a) Hydroxylamine formation CH3 O CCH NH O CCH H3C NOH
CH3 Trimethylacetophenone Trimethylacetophenone imine oxime (b) Oxime formation
Figure 7.6 Examples of N-oxidation.
Oxidative Deamination. Oxidative deamination of amphetamine occurs in the rabbit liver but not to any extent in the liver of either the dog or the rat, which tend to hydroxylate the aromatic ring. A close examination of the reaction indicates that it is probably not an attack on the nitrogen but rather on the adjacent carbon atom, giving rise to a carbinol amine, which eliminates ammonia, producing a ketone:
R2 CHNH2 R2 C(OH)NH2 R2 C=O The carbinol, by another reaction sequence, can also give rise to an oxime, which can be hydrolyzed to yield the ketone. The carbinol is thus formed by two different routes: R2 C(OH)NH2 R2 C=NH R2 CNOH R2 C=O
S-Oxidation. Thioethers in general are oxidized by microsomal monooxygenases to sulfoxides, some of which are further oxidized to sulfones. This reaction is very common among insecticides of several different chemical classes, including carbamates, organophosphates, and chlorinated hydrocarbons. Recent work suggests that members of the CYP2C family are highly involved in sulfoxidation of several organophosphate compounds including phorate, coumaphos, demeton, and others. The carbamate methiocarb is oxidized to a series of sulfoxides and sulfones, and among the chlorinated hydrocarbons endosulfan is oxidized to endosulfan sulfate and methiochlor to a series of sulfoxides and sulfones, eventually yielding the bis-sulfone. Drugs, including chlorpromazine and solvents such as dimethyl sulfoxide, are also subject to S-oxidation. The fact that FMOs are versatile sulfur oxidation enzymes capable of carrying out many of the previously mentioned reactions raises important questions as to the relative role of this enzyme versus that of CYP. Thus, a reexamination of earlier work in which many of these reactions were ascribed to CYP is required.
H2 O +O +H2 O
NH3
PHASE I REACTIONS
P-Oxidation. P -oxidation, a little known reaction, involves the conversion of trisubstituted phosphines to phosphine oxides, for example, diphenylmethylphosphine to diphenylmethylphosphine oxide. Although this reaction is described as a typical CYPdependent monooxygenation, it too is now known to be catalyzed by the FMO also. Desulfuration and Ester Cleavage. The phosphorothionates [(R1 O)2 P(S)OR2 )] and phosphorodithioate [(R1 O)2 P(S)SR2 ] owe their insecticidal activity and their mammalian toxicity to an oxidative reaction in which the P=S group is converted to P=O, thereby converting the compounds from chemicals relatively inactive toward cholinesterase into potent inhibitors (see 11 for a discussion of the mechanism of cholinesterase inhibition). This reaction has been described for many organophosphorus compounds but has been studied most intensively in the case of parathion. Much of the splitting of the phosphorus ester bonds in organophosphorus insecticides, formerly believed to be due to hydrolysis, is now known to be due to oxidative dearylation. This is a typical CYP-dependent monooxygenation, requiring NADPH and O2 and being inhibited by CO. Current evidence supports the hypothesis that this reaction and oxidative desulfuration involve a common intermediate of the phosphooxithirane type (Figure 7.7). Some organophosphorus insecticides, all phosphonates, are activated by the FMO as well s the CYP. Methylenedioxy (Benzodioxole) Ring Cleavage. Methylenedioxy-phenyl compounds, such as safrole or the insecticide synergist, piperonyl butoxide, many of which are effective inhibitors of CYP monooxygenations, are themselves metabolized to catechols. The most probable mechanism appears to be an attack on the methylene carbon, followed by elimination of water to yield a carbene. The highly reactive carbene either reacts with the heme iron to form a CYP-inhibitory complex or breaks down to yield the catechol (Figure 7.8).