Naphthalene preMAP metabolites

The preMAP metabolites from naphthalene were extensively reabsorbed ( 24X) to be excreted with the urine as the premercapturlc acid. The lack of enterohepatlc circulation of intact MAP metabolites of the acetanilide is attributed to microfloral catabolism and not to an inability of these MAP metabolites to be translocated to the tissues (10), because MAP metabolites of the acetanilide were extensively absorbed ( 60%) from the gastrointestinal tracts of germfree and antibiotic treated rats and were excreted unchanged (except for mercapturic acid formation and sulfoxidation) in the urine or bile. Similar studies with naphthalene preMAP metabolites in control rats showed that 70 to 80X of the doses (oral) were absorbed and excreted in the urine mainly as the premercapturlc acid ( 60%) with about 17% as microfloral catabolites (11). When... 

Properties of MAP and preMAP conjugates which influence the extent of the enterohepatlc circulation of intact MAP and preMAP metabolites are not known. Differences in enterohepatlc circulation can be deduced from levels of excretion of MAP and preMAP metabolites by control rats and rats with cannulated bile ducts. Data from 2-chloro- isopropylacetanilide (10) and naphthalene (11) metabolism studies are given in Table II. It is apparent that the acetanilide biliary MAP metabolites were not absorbed from the intestine for excretion as mercapturic acid, but were absorbed as intestinal catabolites of MAP metabolites (23%) and excreted with the urine. 

Of the MAP metabolites tested in vitro, the enzymes studied to date have a specificity for L-cystelne conjugates. A preMAP metabolite (the cysteine conjugate of naphthalene) has been tested only in microorganisms (61) and was a substrate. Tissue C-S lyase exhibits an additional specificity for cysteine conjugates in which the carbon of the xenobiotic moiety attached to the cysteine sulfur be unsaturated (vinyl or aromatic), therefore preMAP metabolites, which lack this aromaticity, should not be substrates for tissue C-S lyase. In vivo evidence that this is the case was obtained in the metabolism of naphthalene (11). C-S lyases associated with the Intestinal microflora, which may involve many different enzymes in a number of different microorganisms, do not exhibit this specificity for aromatic compounds. 

Another variation in GSH conjugate biotransformation has been observed in metabolism of preMAP metabolites of naphthalene (11). 

Figure 6. Catabolism of biliary preMAP metabolites of naphthalene.

Aromatization of preMAP Metabolites. Another spontaneous aromatization process has been observed for preMAP metabolites. PreMAP metabolites of naphthalene (77) and phenanthrene (78) have been shown to spontaneously aromatize to the parent hydrocarbon. The decomposition of 9,10-dihydro-9-hydroxy-10-( cysteinyl)phenanthrene has been proposed to occur through a thiiranium ion as shown in Equation 14. The isolation of the 9,10-dihydrodiol, and a phenol... 

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