Ultimate mutagens

Certain nitro PAHs appear to require metabolism of their N-hydroxy arylamine derivatives in order to induce mutations. For example, while 2-nitrofluorene showed decreased mutagenicity in the nitroreductase-deficient mutant, TA98NR, and in strain TA98/1,8-DNP, its presumed ultimate mutagenic derivative, N-hydroxy-2-aminofluorene was inactive in only strain TA98/1,8-DNP (117). Observations such as these led McCoy t al. (117) to... 

Figure 2. S9-catalyzed metabolites of 5-nitroacenaphthene. Similar oxidation occurs at carbon 2. Metabolites in brackets have not been detected, but may be ultimate mutagens.

Figure 3. Mutagenic activities of the promutagens cis- and Xrms-diallate and sulfallate, the proximate mutagen cis-diallate sulfoxide, and the ultimate mutagen 2-chloroacrolein, assayed with S. typhimurium strain TA 100 sensitive to base-pair substitution mutagens. The diallate isomers and sulfallate are not mutagenic without the S9 mix. S9 mix refers to a microsomal oxidase system prepared from rat liver and appropriate cofactors. The methodology is detailed in Refs. 6, 22, and 29.

Similarly, in vitro tests with CHO cells (with activation) caused an increased frequency of chromosome-damaged cells and SCEs and dose-related decreases in colony formations. In a large number of in vitro tests reviewed by Fishein (ref. 184a), diallate was the more active compound of the two. The ultimate mutagen postulated is 2-chlorocrolein formed via a series of sulfoxidation, rearrangement and 1, 2-elimination reactions ... 

Epoxidation is thought to be the major pathway for benzo[a]pyrene metabolism pertinent to macromolecular interaction. The metabolic attack consists of the cytochrome P-450/P-448-dependent MFO system converting the benzo[a]pyrene molecule into an epoxide the epoxide is acted upon by epoxide hydrolase to form a dihydrodiol, and a second cytochrome MFO reaction gives rise to the ultimate mutagenic/carcinogenicform, benzo[a]pyrene 7, 8-diol-9,... 

Alkyl-triazolines (4.17) were investigated more recently by the same group (Smith et al., 1993). These compounds may be considered as cyclized (Z)-triazenes. It was deduced from very similar dose-response curves for 1-methyltriazoline and 1-methylaziridine and from comparison of the activities of alkyltriazolines, alkyl-triazenes, and alkylaziridines that the ultimate mutagenic intermediate is the aziridinium ion 4.18 and not the diazonium ion (4-14). 

It is known that many chemicals, e.g. polynuclear aromatic hydrocarbons require enzyme modification before becoming biologically active. The production of such so-called "ultimate mutagens or carcinogens" is dependent on a series of inducible enzymes. The induction of these enzymes may increase or decrease the ultimate effect of the parent molecule. These inducible enzyme systems are also under genetic control, raising the question of the existence of susceptible individuals in the general population. 

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... 

Not only is there a requirement for activation but specific monooxygenases must be induced for metabolism to ultimate mutagens. Aroclor 1254, 3-methylcholanthrene, B-naphthoflavone preinduced liver S9 fractions that are capable of near maximal metabolism of the basic fraction to mutagenic intermediates (see Table III). This suggests that the... 

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