Methoxychlor metabolism

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... 

Many xenobiotics contain alkyl groups, such as the methyl (-CH3) group, attached to atoms of O, N, and S. An important step in the metabolism of many of these compounds is replacement of alkyl groups by H, as shown in Figure 7.6. These reactions are carried out by mixed-function oxidase enzyme systems. Examples of these kinds of reactions with xenobiotics include O-dealky-lation of methoxychlor insecticides, N-dealkylation of carbary 1 insecticide, and S-dealkylation of dimethyl mercaptan. Organophosphate esters (see Chapter 18) also undergo hydrolysis, as shown in Reaction 7.3.12 for the plant systemic insecticide demeton ... 

Figure 8.29 Metabolic pathways of methoxychlor in mammals and insects. (Redrawn from Men-zie, C.M., U.S. Department of the Interior Fish and Wildlife Service, Special Scientific Report—Wildlife No. 212, Washington, D.C., 1978.)...

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... 

Because of the broad chemical diversity of compounds in this group, metabolism, detoxification, and excretion pathways are quite variable therefore, the reader should refer to information for a particular compound. As an example, methoxychlor and bisphenol A in low doses have been shown to be... 

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. 

Methoxychlor is slightly toxic to bird species. Met-hoxychlor is highly toxic to fish and aquatic invertebrates. Methoxychlor accumulates in aquatic organisms because these organisms metabolize methoxychlor very slowly. The compound is relatively nontoxic to bees. 

Methoxychlor. Its chemical structure and properties are similar to those of DDT, but it biodegrades more easily. Aquatic organisms metabolize it and transform it into other less toxic substances and therefore it does not lead to significant bioaccumulation phenomena. 

Methoxychlor is a reproductive toxicant. Exposure of young adult male rats to methoxychlor reduced their serum testosterone levels (Murono et al. 2006). It metabolized in the liver into 2,2-bis(p-hydroxyphenyl)-l,l,l-trichloroethane and both methoxychlor and its metabolite were found to exhibit weak estrogenic and antiandrogenic activities. Flynn etal. (2005) have reported that long-term exposure to methoxychlor in diet altered the sexually dimorphic behavior in young rats of both sexes. The study indicated that consumption of sodium solution increased in rats from such exposure. The toxicity of methoxychlor, particularly in the central nervous system, may be attributed to its inhibition of brain mitochondrial respiration which probably is caused by an increased production of reactive oxygen species (Schuh et al. 2005). 

Because partitioning of organic compounds to living organisms is inevitably complicated by certain interfering processes, it is not unusual to anticipate that the correlation between BCF and A ow or S may depend highly on the stability of the compound and the type of organism, as well as the test procedure. Metcalf et al. (77) studied the distribution and metabolism of DDT, DDE, DDD, and methoxychlor in snail Physa), mosquito larvae Culex pipiens quinquefas-... 

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... 

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. 

The slice of liver tissue contains many intact cell layers which maintain hepatic architecture and cell-to-cell interactions, therefore liver slices are expected to provide integrated profiles of phase 1 and phase II metabolites that would be more similar to in vivo metabolism than other in vitro models. This paper describes comparative in vitro metabolism of methoxychlor by precision-cut liver slices from rat, mouse, Japanese quail and rainbow trout. 

In vitro metabolism of methoxychlor by precision-cut rat, mouse, Japanese quail and rainbow trout liver slices... 

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