Carbonium ion metabolites

Figure 2. Possible mechanism of metabolic activation of 2-methyl nitrosopiperi-dine to carbonium ion metabolites...

The role of the carbonium ion metabolites of the nitrosamines in specifying carcinogenic potency can be estimated from an analysis of Vj. The following conclusions have been made ... 

The focus of the next four chapters (Chapters 14-17) is mainly on the theoretical/computational aspects. Chapter 14 by T. S. Sorensen and E. C. F. Yang examines the involvement of p-hydrido cation intermediates in the context of the industrially important heptane to toluene dehydrocyclization process. Chapter 15 by P. M. Esteves et al. is devoted to theoretical studies of carbonium ions. Chapter 16 by G. L. Borosky and K. K. Laali presents a computational study on aza-PAH carbocations as models for the oxidized metabolites of Aza-PAHs. Chapter 17 by S. C. Ammal and H. Yamataka examines the borderline Beckmann rearrangement-fragmentation mechanism and explores the influence of carbocation stability on the reaction mechanism. 

The diol-epoxide contains a reactive carbon center, namely the C-10 position, which can open to form a carbonium ion that is susceptible to nucleophilic attack (Scheme 3.4). The predominant nucleophile among DNA bases is guanine, which preferentially interacts with the carbonium ion at the N2-amine position of guanine to form the BaP-N 2-guanine adduct. The epoxide bond of the diol-epoxide metabolite is particularly resistant to hydrolysis because it is located in the Bay region of the BaP molecule, where steric hindrance prevents the attack of hydrolytic enzymes, such as epoxide hydrolase. 

Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation by liver microsomal enzymes by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to 5-aminoimidazole-4-carboxamide, which is excreted in the urine, and diazomethane. The diazomethane generates a methyl carbonium ion that is believed to be the likely cytotoxic species. Dacarbazine is administered parenterally and is not schedule-dependent. It produces marked nausea, vomiting, and myelosuppression. Its major applications are in melanoma, Hodgkin s disease, and soft tissue sarcomas. 

Nitrosamines are not carcinogenic at the point of application. They require bioactivation. One possible mechanism of biotransformation is by enzymatic transformation to a carbonium ion. Activation is known to proceed first by hydroxylation of an a-carbon. The resulting hydroxyalkyl moiety is eliminated as an aldehyde, and an unstable primary nitrosamine is formed. The unstable nitrosamine ultimately tautomerizes to a carbonium ion. The highly reactive carbonium ion readily alkylates with the nearby cellular macromolecules. Cancer and mutagenicity develop when reactive nitrosamine metabolites alkylate to genetic macromolecules. 

Semustine produces interstrand cross-linking in DNA, generates carbonium ions, and may inhibit several vital enzymatic processes. Alkylation and carbamo-ylation by semustine metabolites interfere with synthesis and function of DNA, RNA, and proteins. 

Figure 25 Illustration of reactive metabolite formation (carbonium ion) through the oxidation, sulfation, and rearrangement of safrole.

No data were located regarding the toxicokinetics of hydrazines in humans after inhalation, oral, or dermal exposure to hydrazines. Inhalation, oral, and dermal studies in animals indicate that hydrazines are rapidly absorbed into the blood. Animal studies also indicate that hydrazines readily distribute to tissues w ithout preferential accumulation at any specific site. Hydrazines with a free amino group are able to react with endogenous alpha-keto acids and in so doing produce a variety of adverse health effects. In vivo and in vitro studies indicate that hydrazines are metabolized by several pathways, both enzymatic and nonenzymatic. Free radical and carbonium ion intermediates are produced during the metabolism of hydrazines and may also be involved in adverse health effects produced by exposure to hydrazines. Limited data from animal studies indicate that metabolites of hydrazines are excreted principally in the urine and expired air. Although the data are limited, animal studies appear to indicate that the toxicokinetics of hydrazines may vary among animal species. 

One of the activation pathways converting BaP to a highly reactive and probably ultimate carcinogenic metabolite, (+ )-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetra-hydrobenzo(a)pyrene ((- -)BPDE(1)), is shown in Figure 2. The vicinal (bay-region) diol epoxides are the ultimate mutagenic and carcinogenic species of alternate PAHs. ( — )BPDE(2) and (- - )BPDE(1) bind only weakly with DNA while (- -)BPDE(1), the major product of the enzymatic oxidation reaction, readily decomposes to form a carbonium ion. This... 

The metabolites III are able to generate stabilized carbonium ions (Scheme 13.4 IV and VI) by loss of hydroxy groups or ester functions as hydroxyl or acid anions. These carbonium ions can react rapidly with nucleophiles (Scheme 13.4 VII). 

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