Methoxychlor demethylation

Methoxychlor Green Sunfish Demethylated and dehydrochlori nated analogs Water 5... 

O-Dealkylation O-Dealkylation of alkyl groups of the ester or ether structures of insecticides occurs frequently, but it also involves an unstable a-hydroxy intermediate as found in N-dealkylation. For example, methoxychlor is O-demethylated by the system (Figure 8.6). O-Dealkylation is known to occur with a wide variety of organophosphates, including certain dimethyl triesters. O-Dealkylation results in detoxification. 

Over the last decades, large amounts of different man-made chemicals which can act as weak estrogens have been released into the terrestrial and aquatic environment and are distributed world-wide. Classical environmental estrogens are pesticides, such as o,p -DDT, and its metabohtes o,p -DDE and o,p -DDD, methoxychlor and its metabolites, chlordecone (Kepone ), dieldrin, Toxaphene, and endosulfan [126, 135, 136]. It is also known that many chemicals with very weak or no measurable estrogenic activity can be metabolized in organisms especially to hydroxylated compounds which may have much more estrogenic potency than the parent compound. Examples are methoxychlor and its mono- and di-demethylated derivatives [126,127] as well as the alkylphenol... 

Chlorinated hydrocarbon insecticides, when dissolved in oil or other lipid, are readily absorbed by the skin and alimentary canal. Although methoxychlor is slowly metabolized to a small extent by pathways similar to those of DDT, the major pathway is by O-demethylation and subsequent conjugation. Methoxychlor has been detected in the blood of agricultural workers. All organochlorines are likely to be excreted in the milk of lactating women. Methoxychlor is excreted mainly in feces, and to a lesser extent in urine. 

Kishimoto, D. and Kurihara, N. 1996. Effects of cytochrome P450 antibodies on the oxidative demethylation of methoxychlor catalyzed by rat liver microsomal cytochrome P450 isozymes isozyme specificity and alteration of enantiotopic selectivity. Pest. Biochem. Physiol., 56, 44—52. 

Kishimoto, D., Oku, A., and Kkurihara, N. 1995. Enantiotopic selectivity of cytochrome P450-catalyzed oxidative demethylation of methoxychlor alteration of selectivity depending on isozymes and substrate concentrations. Pest. Biochem. Physiol., 51,12-19. 

S-CD3)-enantiomer. There is reason to believe that the estrogenic effect of methoxychlor is mainly due to either the S-enantiomer or the R-enantiomeric metabolite. The stereospecific demethylation of methoxychlor is shown below ... 

Enantioselective recognition of mono-demethylated methoxychlor metabolites by estrogen receptor... 

Mono-OH-MXC is a chiral conq>ound in which the carbon atom bridging two benzene rings is the chiral center (Figure 4). It is known that the enzymatic 0-demethylation of methoxychlor into mono-OH-MXC in rat and human livers is enantioselective (10,11). In this metabolic reaction, the (5) enantiomer is predominantly produced by human liver microsomes at n-%1%. The activity of... 

Figure 4, Enantiomers ofmono-demethylated methoxychlor metabolite...

S) k>ih>OH-MXC is predominandy formed by enzymatic 0-demethylation of methoxychlor using rat and human liver microsomes as previously described. Taking into account the result that (S)-mono-OH-MXC is 3 times more active than the (i ) enantiomer, the estrogenic activity of methoxychlor after metabolic activation in vivo should be higher than estimated from the in vitro study using racemic mixtures. 

Table 1. ER binding activity of demethylated methoxychlor metabolites...

Figure 3, Ratio of mono- and bis-demethylated metabolites of methoxychlor formed by precision-cut rat, mouse, Japanese quail and rainbow trout liver slices. The amounts of corresponding glucuronide conjugate are also included...

Methoxychlor is a prochiral compound, and the mono-demethylation reaction would yield chiral metabolites, (Ry and (5)-mono-OH-MXC (Figure 4). Understanding the nature of the P4S0 enzymes contributing for the demethylation reaction of methoxychlor in different animal species, stereoselectivity of the initial demethylation step, which is the conunon metabolic reaction for all animal species tested, was further investigated. 

The metabolic pathways including stereochemistry of methoxychlor metabolism by liver slices obtained in this study are proposed in Figure 6. When the metabolic pathways are expressed in 2-dimentional molecular structures, mouse and quail show quite similar patterns, since the oxidative mono-O-demethylation and subsequent glucuronidation are the main metabolic pathways for both species. However, once the stereological structures are taken into account, the metabolic pathways in these two species turn out to be different, because of the enantioselectivity of the mono-demethylation reactions. Indeed, when the stereological structures are taken into consideration, it is shown that the metabolic pathways of methoxychlor from the four test animal species are all... 

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