Mammals, metabolites

Furthermore, nicotine and benzothiazol were specific contaminants of the seepage water, accompanied by their oxidation products cotinine and benzothiazolones. The tobacco alkaloid cotinine, which is also a mammal metabolite of nicotine, appeared in minor concentrations. Concentrations of nicotine and cotinine ranged from 550 to 710 pg/L and from 90 to 180 pg/L, respectively. As compared to the seepage water samples no signficant reduction of the concentrations in the leakage water was observed. The origin of benzothiazolone can be attributed either to an oxidation of benzothiazol or to the hydrolysis of substituted benzothiazols like 2-methylthiobenzothiazol, a common rubber additive. 

There are very limited data on the kinetics and metabolism of organotins in laboratory mammals. A widespread distribution of organotins throughout body tissues has been observed. Transplacental transfer seems to occur, whereas transfer across the blood-brain barrier is limited, since brain levels are usually low. The only compound for which data are available on metabolites is dibutyltin, which has butyl(3-hydroxybutyl)tin as its major metabolite. Limited information suggests quite rapid metabolism and elimination, with half-lives of several days. Much of an oral dose of dioctyltin was eliminated in the faeces, with the remainder in urine. 

Many of the phase 1 enzymes are located in hydrophobic membrane environments. In vertebrates, they are particularly associated with the endoplasmic reticulum of the liver, in keeping with their role in detoxication. Lipophilic xenobiotics are moved to the liver after absorption from the gut, notably in the hepatic portal system of mammals. Once absorbed into hepatocytes, they will diffuse, or be transported, to the hydrophobic endoplasmic reticulum. Within the endoplasmic reticulum, enzymes convert them to more polar metabolites, which tend to diffuse out of the membrane and into the cytosol. Either in the membrane, or more extensively in the cytosol, conjugases convert them into water-soluble conjugates that are ready for excretion. Phase 1 enzymes are located mainly in the endoplasmic reticulum, and phase 2 enzymes mainly in the cytosol. 

In mammals, dieldrin and endrin are also converted into keto metabolites (Figure 5.5). In the rat, the keto metabolite is only a minor product, which, because of its lipophilicity, tends to be stored in fat. With endrin, a keto metabolite is formed by the dehydrogenation of the primary monohydroxy metabolite. In mammals, the trans diol of dieldrin is converted into a diacid in vivo (Oda and Muller 1972). 

Some data on cyclodiene toxicity is presented in Table 5.9. Aldrin and dieldrin have similar levels of acute toxicity indeed, the toxicity of aldrin has been largely attributed to its stable metabolite, dieldrin. Dieldrin is highly toxic to fish, mammals. 

In mammals, there is evidence that hydroxy PCBs are transferred across the placenta into the fetus, where they accumulate (Morse et al. 1995). In an experiment with pregnant rats exposed to 3,3, 4,4 -TCB, substantial levels of 4 OH,3,3, 4,5 -TCB accumulated in the fetus, with concomitant reduction in levels of T4. This was due to competitive binding of the PCB metabolite to TTR, thereby excluding T4. Similar... 

Bromo-6-(2-imidazolin-2-ylamino)quinoxaline (brimonidine 119) afforded 5-bromo-6-guanidinoquinoxaline (120) as a major metabolite from several mammals.803... 

Just like mammals, birds have a delayed reaction to lipotropHc pesticides such as OCPs and their metabolites. These toxic substances dissolve and accumulate in the fatty tissues of well-fed birds, and are comparably harmless in this form. However, once the bird starts using the stored fat (at the end of a long flight or when laying eggs), the substances are carried through the bloodstream to the brain, liver, or yolk of the egg, and poison all the systems [1]. In particular, well-fed raptors have lower DDE concentrations in their liver (0.5 mg/kg) than less well-fed (3.5 mg/kg) and emaciated birds (7.3 mg/kg) [6]. 

In the case of deca-BDE, its suggested degradation process in mammals consists of a first reductive debromination where one, two or three bromine atoms can be replaced by hydrogen atoms followed by an oxidation to form hydroxylated metabolites, which are presumably formed from an intermediate epoxy [52]. This study detected traces of three nona-BDEs, which may be an indication of reductive debromination as a first step of degradation, and thirteen hydroxylated metabolites. Otherwise, the possibility of a deca-BDE oxidation as a first step to form the epoxy without an intermediate reductive debromination is also suggested [52]. The study conducted by Morck et al. [53] detected several hydroxylated products, from methoxy-hydroxy-pentabrominated to methoxy-hydroxy-heptabrominated compounds, which coincide with part of the metabolites obtained by Sandholm et al. [52]. In addition, both authors found that methoxy and hydroxy substituents are always on the same aromatic ring when both are present. Moreover,... 

Regarding the reductive debromination as the first step of deca-BDE degradation in mammals, Huwe and Smith [54] detected the formation of different PBDEs (three nona-BDEs, four octa-BDEs and one hepta-BDE) from deca-BDE degradation in rats, which also suggests the existence of a reductive debromination process as the first step in deca-BDE degradation in mammals. In this case, it was not identified whether the specific enzymatic system responsible for the reductive debromination and the corresponding analyses to detect the formation of hydroxylated metabolites were not carried out. 

Moreover, considering the involvement of Cyp P450 in the first step of deca-BDE degradation by the fungus and previously reported for deca-BDE, BDE-154 and BDE-100 in mammals [50-53], it was expected that PBDE mixtures degradation products by the fungus would be very similar to those detected in degradation processes in mammals. These products correspond to hydroxylated and methoxy-hydroxylated metabolites. 

Recently, Voogt et al. [91] have reported on the d5-pathway in steroid metabolism of Asterias rubens. These workers established the existence of the d5-pathway (Scheme 20), analogous to the pathway found in mammals this conclusion was based on the observation that radiolabeled cholesterol (1) was converted to pregnenolone (112), 17a-hydroxypregnenolone (141), and androstenediol (142). Labeled pregnenolone was converted additionally to progesterone (129). Androstenediol (142) was the main metabolite of de-hydroepiandrosterone (143), a reaction catalyzed by 17/i-hydroxysteroid dehydrogenase (17/1-HSD). The metabolic conversion of androstenedione (131) to testosterone (132) is also mediated by 17/J-HSD and is related to... 

The title compound, 88, the main metabolite of 13-cis-retinoic acid in mammals, has been synthesized27 as before via condensation of acetone-1,2,3-13C3 with 3,7-dimethyl-2,6-octadienal (citral), 89 (equation 33). 

---