Detoxification pathways

A wide diversity of herbal remedies have purported abilities to stimulate defense functions. Complexes of carbohydrate and lignin, which are present in some herbs, modulate enteric immune functions (Kiyohara et al, 2000), and the changes in cytokine secretion (Matsumoto and Yamada, 2000) can trigger systemic responses. The polysaccharides present in other herbal medicines augment production of immunoglobulin (Ig) A by the Peyer s patches in the small intestine (Sakushima et al, 1997 Yu et al, 1998). The responses of the enteric immune system to lectins are variable (Pusztai 1993), and can elicit systemic responses (Lavelle et al, 2000). Other phytochemicals provide protection by inducing detoxification pathways in mucosal cells (Williamson et al, 1998). 

Table IV also contains results of UV absorption studies of hydroxylation effects on the DNA intercalative binding of ben-zo[a]pyrene metabolites and metabolite model compounds. The most important feature of these results is that hydrolysis of BPDE to BPT causes a four-fold reduction in the intercalation association constant. Of all the BP derivatives studied, the tetrol has the lowest binding constant for intercalation. The small binding constant of the tetrol compared with BPDE, coupled with the DNA catalyzed hydrolysis of BPDE to the tetrol may provide a detoxification pathway for removal of a portion of unreacted intercalated BPDE.

Rhodanese is widely distributed in the body, but activity levels in mammals are highest in the mitochondrial fraction of liver. Rhodanese activity levels in catalyzing the transformation of thiosulfate to thiocyanate are limited by the availability of sulfur. Minor detoxification pathways for cyanide include exhalation in breath as HCN, and as C02 from oxidative metabolism of formic... 

The metabolism of 77-hexane takes place in the liver. The initial reaction is oxidation by cytochrome P-450 isozymes to hexanols, predominantly 2-hexanol. Further reactions convert 2-hexanol to 2-hexanone, 2,5-hexanediol, 5-hydroxy-2-hexanone, 4,5-dihydroxy-2-hexanone and the neurotoxicant 2,5-hexanedione. Hydroxylation at the 1- and 3- positions can be considered detoxification pathways hydroxylation at the 2- position is a bioactivation pathway. A diagram of the proposed pathway for mammalian metabolism of -hexane is presented in Figure 2-3. 

Detoxification pathways (oxidation/reduction/hydrolysis/conjugation) Toxification pathways (oxidation/reduction/hydrolysis/conjugation)... 

Marsh KJ, Wallis IR, Andrew RL, Foley WJ (2006a) The detoxification limitation hypothesis where did it come from and where is it going J Chem Ecol 32 1247-1266 Marsh KJ, Wallis IR, McLean S, Sorensen JS, Foley WJ (2006b) Conflicting demands on detoxification pathways influence how common brushtail possums choose their diets. Ecology 87 2103-2112... 

Sometimes CYPs can also produce reactive metabolite species that, instead of undergoing the normal detoxification pathway, can act as irreversible CYP inhibitors, thus causing toxicity. Such reactive metabolites that cause CYP inactivation are called MBI and are described in Chapter 9. Mechanism-based enzyme inhibition is associated with irreversible or quasi-irreversible loss of enzyme function, requiring synthesis of new enzymes before activity is restored. The consequences of MBI could be auto-inhibition of the clearance of the inactivator itself or prolonged inhibition of the clearance of other drugs that are cleared by the same isozyme. There may also be serious immunotoxicological consequences if a reactive intermediate is covalently bound to the enzyme. Therefore, screening of new compounds for MBI is now a standard practice within the pharmaceutical industry. 

McFadden SA. 1996. Phenotypicvariation in xenobiotic metabolism and adverse environmental response Focus on sulfur-dependent detoxification pathways. Toxicology 111 43-65. 

Often metabolites are more readily excreted from the body than the chemical that entered it, and chemical pathways leading to such metabolites are called detoxification pathways the quicker the chemical is eliminated, the less chance it has to cause injury. 

Moreover, a variety of other drugs of synthetic origin, containing a phenyl substituent, do not suffer any aromatic hydroxylation, neither in animal systems nor in microbial systems they often correspond to trisubstituted amino group containing derivatives, where -dealkylation is a major detoxification pathway and probably results in products exhibiting a sufficient decrease in hydrophobicity. 

For many chemicals, their metabolism is the major determinant of the risk and for a number of hazardous compounds, there is a considerable knowledge from experimental studies on the relationship between metabolism and toxicity. In particular, in vitro studies using cell cultures, subcellular fractions, or pure enzymes have provided information on the nature of reactive intermediates as well as on detoxification pathways. Moreover, the significance of these processes has been demonstrated in several species of experimental animals and humans. 

Using pig and human microsomes and cDNA-expressed human flavin-containing monooxygenase, Lin and Cashman demonstrated a metabolic detoxification pathway that converts tyramine into the HA derivative, 20, and the anti oxime, 21, which was sufficiently stable to permit its chemical characterization". ... 

Cytotoxic activity. Water extract of the dried root, in cell culture, was inactive on CA-9KB, ED50greater than 0.1 pg/mL The methanol extract was active on Leuk-P388, ED50 0.57 pg/mL L Detoxification activity. Phenolic resin, in increasing levels, was mixed with alfalfa pellets and fed to wood rats. Three detoxification pathways and urine pH, which are related to detoxification of allelochemicals, were measured. The excretion rate of two-phase II detoxification conjugates, glucu-... 

Crameri, A., S.A.Raillard, E.Bermudez and W.P.Stenuner. (1998) Molecular evolution of an arsenate detoxification pathway by DNA shuffling. Nature, 391, 288-291. 

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