Methyl hydroxylation, metabolic

It is known that nitrosamines with side-chains longer than methyl are metabolically hydroxylated on virtually every carbon. For example, the urinary metabolites in the rat of di-n-butylnitrosamine include the glucuronides of the following hydroxylated nitrosamines (42). 

Enantioselective metabolism oxidative deamination and reduction to 2-ol (R) benzylic 2 -methyl hydroxylation C-3 or 4 aromatic hydroxylations (S)... 

After peroral application to rats silicon compounds 86b and 87b were absorbed and subsequently eliminated in the urine as both phenyl- and methyl-hydroxylated metabolites. Metabolic studies of 86b and 87b were carried out with the [14C] methyl-silicon label. 

In other weed biotypes, resistance to triazine herbicides is likely conferred by rapid metabolism of the herbicides to inactive compounds. A chlorotoluron-resistant biotype of blackgrass (slender foxtail) was cross-resistant to various other groups of herbicides, including triazines (Kemp et al., 1990). The mechanism of chlorotoluron resistance was Cyt P450-based enhanced oxidative metabolism through /V-demethylation and ring-methyl hydroxylation (Moss and Cussans, 1991). Consequently, it is likely that resistance to triazines in this blackgrass biotype is also due to enhanced herbicide detoxification. 

Knodell, R.G., S.D. Hall, G.R. Wilkinson, and F.P. Guengerich (1987). Hepatic metabolism of tolbutamide Characterization of the form of cytochrome P-450 involved in methyl hydroxylation and relationship to in vivo disposition. J. Pharmacol. Exp. Ther. 241, 1112—1119. 

P450 2C18 has low catalytic activity in tolbutamide methyl hydroxylation [803]. P450 2C18 is active in phenytoin metabolism, having an enzyme efficiency for 4-hydroxylation... 

We analyzed the metabolism of chlortoluron in CYPlAl rice phmts and control Nipponbare plants. On die 6th day of incubation, the mean amount of chlortoluron in the CYPlAl rice plants was equivalent to only 1.5% of die added radioactivity. The total amount of metabolites, including N-demethylated (DM), ring-methyl hydroxylated (OH), N-demethylated and ring-methyl hydroxylated (DMOH), and conjugated (Ori) compound was 24.6% added (Fig. 3A). However, in control Nipponbare plants, the amount of chlortoluron was 8.1% of the added radioactivity, and that of the metabolites was 4.5%. 

Figure 3. Metabolism of C-Iabeled herbicides in CYPIAI rice plants analyzed by thin-layer chromatography (TLC). (A) Relative amoimts of chlortoluron and its metabolites in plant extracts. (B) Relative amounts of norflurazon and its metabolites in plant extracts. CT, chlortoluron DM, N-demethylated chlortoluron OH, ring-methyl hydroxylated chlortohnon DMOH, N-demethylated and ring-methyl hydroxylated chlortoluron NF, norflurazon -metNF, demethylated norflurazon Ori, origin of the TLC plate (conjugated confounds). Quantity of radioactivity added to the plants was defined as 100%. Values are averages of 3 independent experiments.

Acetolactate synthase (ALS) is the enzyme target site of the sulfonyl-ureas. In common with the imidazolinone aryl carboxylates, these herbicides inhibit valine and isoleucine biosynthesis. The imidazolinones are exemplified by Assert (8), which consists of a mixture of m- and p-isomers. The selectivity of ALS inhibitors invariably can be accounted for by differential metabolism or uptake or related phenomena rather than by any significant inherent difference in the properties of the ALS enzymes of crop and weed species. Assert is another example of a herbicide activated in plants by deesterification to the phytotoxic acid, and susceptible species such as Avena fatua (wild oat) are unable to metabolize the molecule further. Facile ring-methyl hydroxylation to the m- and p-benzyl alcohols, however, followed by glycosylation confers tolerance to maize and wheat." ... 

In man, the metabolic pathways of mepirizole were distinct from those in experimental animals, since hydroxylation on each of the aromatic rings did not occur in man. Compound (752) was obtained by oxidation of the 3-methyl group to the carboxylic acid (a similar process occurs with 5-methylpyrazole-3-carboxylic acid, an active metabolite of 3,5-dimethylpyrazole). However, the carboxylic acid metabolite of mepirizole had no analgesic activity and did not decrease blood glucose. 

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

Although the metabolism of vanillate generally involves de-O-methylation to 3,4-dihy-droxybenzoate followed by intradiol ring hssion, in Acinetobacter Iwoffii vanillate is hydroxylated to 3-0-methyl gallate, which produces pyruvate and oxalacetate in reactions that have already been noted (Sze and Dagley 1987). 

The proposed pathways for methyl-substituted quinolines differ from those shown in Fig. 23, even for the same culture, and most particularly, the fact that no C—N bond cleavage has been observed in most of the strains. A limited number of methylquinolines can be hydroxylated due to the inhibiting and blocking effect of the methyl group, particularly at position 2. So, neither P. aeruginosa QP nor P. putida QP could metabolize 2-methylquinoline however, a new strain of Pseudomonas (MQP) isolated by Grant and Al-Najjar [328] was reported to be able to transform 2-methylquinoline, yielding... 

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