Metabolite activation reactions

The probable metabohc defect in type I tyrosine-mia (tyrosinosis) is at himarylacetoacetate hydrolase (reaction 4, Figure 30-12). Therapy employs a diet low in tyrosine and phenylalanine. Untreated acute and chronic tyrosinosis leads to death from liver failure. Alternate metabolites of tyrosine are also excreted in type II tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine aminotransferase (reaction 1, Figure 30-12), and in neonatal tyrosinemia, due to lowered y>-hydroxyphenylpyruvate hydroxylase activity (reaction 2, Figure 30-12). Therapy employs a diet low in protein. 

In addition to influencing hydrocarbon metabolite-DNA reactions, the physical binding properties of hydrocarbon metabolites covalently bound to DNA may also be important to carcinogenic activity. The covalent binding of ultimate carcinogens derived from BP and DMBA to DNA produces adducts with tt binding properties similar to those of naturally occurring nucleotides. These adducts... 

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

The same metabolite, 11.123, is produced when a carboxy substituent is present at C(3) (i.e., 11.122, R = COOH) [147][148], The mechanism of this activation reaction is also concerted, but, in this case, more extended, with involvement of the carboxylate group and decarboxylation simultaneous with ring cleavage. In vivo in rats, this reaction was clearly slower than for the unsubstituted analogue, with plasma levels of both the prodrug and the metabolite 11.123 being maintained at comparable levels for 24 h. 

ATP and the other nucleoside triphosphate coenzymes not only transfer phosphate residues, but also provide the nucleotide components for this type of activation reaction. On this page, we discuss metabolites or groups that are activated in the metabolism by bonding with nucleosides or nucleotides. Intermediates of this type are mainly found in the metabolism of complex carbohydrates and lipids. 

Conjugation reactions usually involve metabolite activation by some high-energy intermediate and have been classified into two general types type I, in which an activated conjugating agent combines with the substrate to yield the conjugated product, and type II, in which the substrate is activated and then combines with an amino acid... 

Reactive metabolites include such diverse groups as epoxides, quinones, free radicals, reactive oxygen species, and unstable conjugates. Figure 8.2 gives some examples of activation reactions, the reactive metabolites formed, and the enzymes catalyzing their bioactivation. 

These reactive metabolites can bind covalently to cellular macromolecules such as nucleic acids, proteins, cofactors, lipids, and polysaccharides, thereby changing their biologic properties. The liver is particularly vulnerable to toxicity produced by reactive metabolites because it is the major site of xenobiotic metabolism. Most activation reactions are catalyzed by the cytochrome P450 enzymes, and agents that induce these enzymes, such as phenobarbital and 3-methylcholanthrene, often increase toxicity. Conversely, inhibitors of cytochrome P450, such as SKF-525A and piperonyl butoxide, frequently decrease toxicity. 

These resemble the penicillins structurally, in mode of action and in general lack of toxicity. They are primarily excreted by the kidney by tubular secretion and some also by glomerular filtration (e.g. cephalothin) or only by glomerular filtration (e.g. cefazolin). Cefoperazone is excreted by the bile. Cefotaxime undergoes hepatic biotransformation to active metabolites. Hypersensitivity reactions are qualitatively similar to those of the penicillins, but the epileptogenic potential is less. 

Disposition in the Body. Readily absorbed after oral administration. It is extensively metabolised by oxidation to carboxyprimaquine which is the major plasma metabolite. Other reactions which may occur are demethylation and oxidation to the 5,6-diol, which is then converted to an active quinone, V-dealkylation to 8-amino-6-methoxyquinoline, and iV-acetyla-tion. Less than 5% of a dose is excreted in the urine unchanged in 24 hours. 

Many types of liver injury are caused by a number of biochemical reactions of toxicants or their active metabolites. Such reactions inclnde covalent binding, lipid peroxidation, inhibition of protein synthesis, pertnrbation of calcium homeostasis, disturbance of biliary prodnction, and a variety of immunologic reactions. The types of liver injury from such biochemical reactions include steatosis (fatty liver), liver necrosis, cirrhosis, cholestasis, hepatitis, and carcinogenesis. The toxicants that cause these injuries are discussed in brief. 

Potential toxicity of metabolites may depend on activation reactions in resistant vs sensitive strains. Reactive metabolites generated in resistant plants are generally labile and would not likely be incorporated into animals in measurable levels. In animals, the resultant toxicity of a compound may depend on the proportion converted into active metabolites in sensitive vs resistant species of test animals. (See Gillette, Biochemical Aspects, herein). 

For an oscillating metabolic pathway, there are two reactions or two segments of reactions (and therefore the enzymes that catalyze these reactions), which are subject to metabolite activations/inhibitions. The enzymes involved are called osciUophors. 

Corrosion associated with the action of micro-organisms present in the corrosion system. The biological action of organisms which is responsible for the enliancement of corrosion can be, for instance, to produce aggressive metabolites to render the environment corrosive, or they may be able to participate directly in the electrochemical reactions. In many cases microbial corrosion is closely associated with biofouling, which is caused by the activity of organisms that produce deposits on the metal surface. 

EtOH) was examined in detail by Mead and Koepfli, who, from its reactions and the resemblance of its absorption spectrum to that of 2-hydroxy-6-methoxy-4-methylquinoline, regard it as Z-2 -hydroxyquinine (2 -hydroxy-6 -methoxy-3-vinylruban-9-ol). According to P. B. Marshall, this metabolite is inactive in chick malaria, but Kelsey efaZ. (1946) find that at a dosage of 40-70 mgm./kilo./day, it exercises about the same degree of suppression as 15 mgm./kilo./day of quinine, and quote E. K. Marshall for the observation that it has about one-twentieth the activity of quinine in the malaria of ducks. 

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