Metabolite detoxification reactions

Alternative metabolic pathways involve ring-oxidation and peroxidation of arylamines. Although ring-oxidation is generally considered a detoxification reaction, an electrophilic iminoquinone (X) can be formed by a secondary oxidation of the aminophenol metabolite (18,19). Lastly, reactive imines (XI) can be formed from the primary arylamines by peroxidase-catalyzed reactions that involve free radical intermediates (reviewed in 20). 

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). 

Biotransformation and generation of reactive intermediate metabolites are associated with a variety of toxicities and idiosyncratic reactions.37 Toxicologists should always consider how drug disposition and fate contribute to toxicity, as target organ dosimetry, biotransformation, and detoxification reactions can be important determinants of toxicity. In all cases, understanding how biotransformation may differ across species, with emphasis on human metabolism, is an important component in determining whether preclinical effects are predictive of and relevant for human safety evaluation. 

It should be noted that this system is only a first approximation to the complex metabolic processes that occur in vivo, and in particular there is little account taken of the phase 11 detoxification reactions. Such factors should be considered when interpreting positive in vitro results that are only seen in the presence of S9 mix. It should be noted that some cytochrome P450s in induced S9 are so greatly elevated above the levels in normal liver (see Table 11.1) that reactive metabolites may be produced in significant quantities in vitro that would be negligible in normal livers in vivo. 

Molecular oxygen is used in a variety of oxidative detoxification reactions aromatic hydroxylation aryl oxidation O- and M-deaUcylation deamination and sulfoxidation. These reactions either modify functional groups or add oxygen to the foreign compound, forming metabolites that lack pharmacological activity and which are more rapidly eliminated in the urine because of increased water solubility. 

Multiple forms of cytochrome P-450 have differing catalytic activities with respect to formation of primary metabolites of BaP. Six different forms of cytochrome P-450 isolated from rabbit liver microsomes catalyzed the oxidation of BaP at different rates and produced different ratios of individual phenolic and quinone metabolites (572, 491). Different forms of cytochrome P-450 also showed differing activities and stereospecificity in metabolism of the —)-tranS 7,8-dihydrodiol to diol epoxides 101). The specificity of differing inducible forms of cytochrome P-450 in the metabolism of BaP is important since the predominance of a given form may influence the balance between activation and detoxification reactions. 

The membrane-attached cytochrome P450 enzymes are involved in a significant fraction of events associated with drug metabolism. Most of the cytochrome P450 (CYP) catalyzed reactions lead to the detoxification of xenobiotics, by forming hydrophilic metabolites that can be readily excreted from the body. 

Fig. 9.15. Metabolism of acephate (9.82) in mammals [156]. Pathway a leads to toxification by producing methamidophos. Pathways b-d are reactions of detoxification that lead to an O-demethyl, a demethylthio, and a deacetylamino metabolite, respectively.

An a priori classification of these various reactions as either toxification or detoxification is simply impossible, since each product from these various pathways may be toxic or not depending on its chemical properties and own products. Furthermore, the biological context plays a critical role [154], yet this role, best viewed as the influence of biological factors on the relative importance of competitive routes of metabolism, is often underplayed by those who venture to make predictions of metabolic outcome. Indeed, in the cascade of intertwined metabolic routes exemplified by haloalkenes, a small difference in pathway selectivity at an early metabolic crossroad may be amplified downstream, giving rise to major differences in relative levels of metabolites and overall toxicity. 

In rats administered 2-bromoethylamine, urinary aziridine accounted for 15-45% of the dose. The carbamate 11.135 was not detected in urine, whereas oxazolidin-2-one and a tertiary metabolite, 5-hydroxy oxazolidin-2-one, accounted for 0 - 20% and 2 - 12% of the dose, respectively [156], The innocuity of oxazolidin-2-one led to the suggestion that either aziridine or 2-bromoethylamine itself is responsible for mitochondrial toxicity. These studies show that the nephrotoxic 2-haloethylamines undergo two competitive cyclizations with halide elimination, one probably a reaction of toxification, the other clearly a reaction of detoxification. 

Quinones and other xenobiotics are metabolized primarily in the liver, and the end products are water-soluble compoimds that are excreted from the body. The first step in metabolism is usually an oxidative process (phase I detoxification), after which further oxidation and conjugation can occur (phase II detoxification). Although those reactions normally yield easily excreted products, some steps in the metabolic pathway may generate metabolites that are more toxic than the parent comporuid. 

Acute poisoning only occurs when the detoxification mechanism is overwhelmed. This reaction is enhanced by giving sodium thiosulfate and sodium nitrate intravenously as 20% solutions in a 3 1 ratio, which is a recommended antidote for acute cyanide poisoning. It is the thiocyanate metabolite that causes chronic disease when cyanide forage is ingested over an extended period. 

---