Disease relevance of 3MC

• Two human homologs of the Escherichia coli AlkB protein, denoted hABH2 and hABH3, were recently shown to directly reverse 1-methyladenine (1meA) and 3-methylcytosine (3meC) damages in DNA [1].
• Salmonella bacteria were detected by both cultivation and PCR-hybridization in 68% (17 of 25) of the positive samples that were preenriched in TSB, in 73% (11 of 15) of the positive samples preenriched in 3MC broth, and in 24% (6 of 25) of the positive samples enriched in RV10 [2].
• The effectiveness of combined chemoimmunotherapy with ifosfamide derivative CBM-4A and granulocyte-macrophage colony-stimulating factor (GM-CSF) was investigated in two experimental tumor models, 3MC-induced MHC class I+ sarcoma Mc12 and HPV16 E6/E7 oncogene-induced MHC class I- carcinoma MK16, transplanted in syngeneic mice [3].

High impact information on 3MC

• Thus, the known substrates of these enzymes now include 3-methylthymine in DNA, as well as 1-methyladenine and 3-methylcytosine, which all have structurally similar sites of alkylation [4].
• Recent work has uncovered a novel DNA repair enzyme: the AlkB protein of Escherichia coli, which oxidises the methyl groups of 1-methyladenine and 3-methylcytosine to hydroxymethyl moieties; the oxidised groups are subsequently released as formaldehyde, regenerating the unmodified bases [5].
• 1-OH-3MC and 2-OH-3MC, formed in the metabolism of 3MC by liver microsomes from untreated, phenobarbital (PB)-treated and 3MC-treated male Sprague-Dawley rats, were first isolated as a mixture by reversed-phase HPLC and subsequently separated by normal-phase HPLC [6].
• The regiospecificity and stereoselectivity of testosterone hydroxylation by hepatic microsomes prepared from control, PB, 3MC and 2AAF treated chick embryos has been analysed [7].
• This interaction explains the decrease of 3MC-induced CYP1A1 expression [8].

Chemical compound and disease context of 3MC

• Escherichia coli AlkB is a DNA/RNA repair enzyme containing a mononuclear Fe(II) site that couples the oxidative decomposition of alpha-ketoglutarate (alphaKG) to the hydroxylation of 1-methyladenine or 3-methylcytosine lesions in DNA or RNA, resulting in release of formaldehyde and restoration of the normal bases [9].

Biological context of 3MC

• Our results suggest that 3-methylcytosine could be responsible, at least partially, for the killing and the mutagenesis observed after cell treatment by alkylating agents [10].
• In vitro methylation of rat liver tRNA-synthesis of 3-methylcytosine and 1-methylhypoxantheine [11].

Anatomical context of 3MC

• We showed in Caco-2 cells that addition of RA significantly decreased 3MC-induced CYP1A1 expression by -55% for mRNA level and -30% for promoter and enzymatic activities [8].
• Eleven P-450s, 3MC and PB microsomes preferentially formed 1R,2R-diol enantiomer (80-96%) [12].
• Rat liver epithelial cells resistant to the chemical carcinogen 3MC, termed F258/3MC cells and generated by long-term exposure of parental F258 cells to the PAH, were characterized, especially with respect to expression of multidrug resistance transporters such as P-glycoprotein, MRP1 and MRP2 [13].
• Benzo(a)pyrene hydroxylase activity was found in the bone marrow of control and 3MC-induced New Zealand white rabbits [14].

Associations of 3MC with other chemical compounds

• F258/3MC cells were found to be cross-resistant to other PAHs such as BP and dimethylbenz(a)anthracene but remained sensitive to known substrates of multidrug resistance efflux pumps such as doxorubicin and vincristine [13].

Gene context of 3MC

• The Escherichia coli AlkB protein encoded by alkB gene was recently found to repair cytotoxic DNA lesions 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) by using a novel iron-catalysed oxidative demethylation mechanism that protects the cell from the toxic effects of methylating agents [15].
• The benzyloxyresorufin-O-deethylase (BROD) activity was decreased after incubation with 3MC but increased with beta N [16].
• Induction of AHH activity of female rats administered 3MC was higher than that of male rats [17].
• In addition, P-glycoprotein and MRP2 mRNA levels were not, or only barely detected, in F258/3MC cells and in their parental counterparts whereas these PAH-resistant and sensitive cells showed closed levels of MRP1 mRNAs and activity [13].
• The alkoxyresorufin-O-dealkylase activity was measured in the S9 fraction of lung slices incubated for 24 h with 10(6) mol/L 20-methylcholanthrene (3MC) or beta-naphthoflavone (beta N) [16].

Analytical, diagnostic and therapeutic context of 3MC

• R/S enantiomer ratios of 1-OH-3MC formed in the metabolism of 3MC by three rat liver microsomal preparations were determined by CSP HPLC: 35:65 (control), 39:61 (PB treated) and 46:54 (3MC treated) respectively [6].
• At the maximum of the induction effect after pretreatment with the highest dose of 3MC no morphological alterations in the liver could be observed by light and electron microscopy [18].

References