Demethylation, inhibition

Sutton, D., Butler, A.M., Nadin, L. and Murray, M. (1997) Role of CYP3A4 in human hepatic diltiazem N-demethylation inhibition of CYP3A4 activity by oxidized diltiazem metabolites. Journal of Pharmacology and Experimental Therapeutics, 282 (1), 294-300. 

In conclusion it may be stated that experiments with barley powdery mildew have confirmed the validity of mechanism of action studies with azoles on yeasts and non-obligate fungi. Even though there is a structural difference in the end-product of sterol biosynthesis, this does not affect the concept of C-14-demethylation inhibition. 

Pulukuri SM, Rao JS. Small interfering RNA directed reversal of urokinase plasminogen activator demethylation inhibits prostate tumor growth and metastasis. Cancer Res 2007 67 6637 646. 

Desipramine [50-47-5] (35) and nortriptyline [72-69-5] (36) are demethylated derivatives and principal metaboHtes of (32) and (33), respectively. Both compounds possess less sedative and stronger psychomotor effects than the tertiary amine counterparts, probably because tricycHcs containing secondary amine groups generally show greater selectivity for inhibiting the reuptake of norepinephrine compared with the reuptake of serotonin. Protriptyline [438-60-8] (37), a stmctural isomer of nortriptyline, is another important secondary amine that displays a similar clinical profile. 

Dacarbazine is activated by photodecomposition (chemical breakdown caused by radiant energy) and by enzymatic N-demethylation. Formation of a methyl carbonium ion results in methylation of DNA and RNA and inhibition of nucleic acid and protein synthesis. Cells in all phases of the cell cycle are susceptible to dacarbazine. The drug is not appreciably protein bound, and it does not enter the central nervous system. 

Cocaine-mediated hepatotoxicity has been associated with the conversion of cocaine to norcocaine and further oxidation products. The enzymes involved in in vitro hepatic oxidative N-demethylation of cocaine (192) were investigated (237), and two different enzymatic pathways appear to be important in the formation of the hepatotoxic metabolite. Cytochrome P-450 monooxygenases accomplish the direct N-demethylation of cocaine to norcocaine (194) as confirmed by induction and inhibition studies (Scheme 42). The second pathway for cocaine N-demethylation involves formation of cocaine /V-oxide (193) as an intermediate and two enzymes. A flavin-containing monooxygenase is first thought to convert cocaine to cocaine /V-oxide, followed by cytochrome P-450-... 

Anders, M.W. and Mannering, G.J. Kinetics of the inhibition of the N-demethylation of ethylmorphine by 2-diethylamino-ethyl 2,2-diphenyl valerate HC1 (SKF-525A) and related compounds. Mol. Pharmacol. (1966) 2 319-327. 

We find that demethylation can be inhibited with 2% v/v of alkylating agent, such as benzyl chloride, added to the benzene phase (Figure 5). In this case, we observe only 3-(benzylthio)cyclohexene... 

RT-PCR often brain tumors reveals none positive for CYP3A4 (Knupfer et al., 1999). Phenobarbital induces CYP3A1 mRNA in rat striatum and cerebellum (Schilter et al., 2000). Rat and human brain microsomes demethylate amitriptyline. Chemical and antibody inhibition suggests CYP3A4 is responsible (Voirol et al., 2000). 

Fig. 7. The model proposed by Szyf to explain the unmethylated status of active genes (for references and further details see Section 5.1). a) Inhibition of acetylation of the tails of core histones prevents active demethyiation. (b) When histone tails are acetylated, as in transcriptionally active chromatin regions, the demethyiase binding to the regions is enhanced, and the DNA is actively demethylated.

The mechanism of inhibition of these protozoal infections by the most active drugs, puromycin and the aminonucleoside, is not known. Puromycin and nucleocidin both interfere with protein synthesis, but the aminonucleoside does not. It is known to be demethylated to 3 -amino-3-deoxyadenosine, which is phosphorylated and interferes with nucleic acid metabolism (see above). Whether puromycin must be converted to the aminonucleoside before it can inhibit protozoa has not been established. Some purine analogues known to interfere with nucleic acid metabolism, however, are less effective as antiprotozoal agents, even in vitro, perhaps because their effects are primarily on the de novo pathway which many, if not all, protozoa do not use [406]. 

Although termed "SI" or "EBI" compounds, the latter referring to ergosterol biosythesis inhibitors, these compounds do not all inhibit ergosterol biosynthesis at the same metabolic site (Fig. 2). For instance, the fungicide tridemorph, unlike most EBI compounds, does not inhibit demethylation at C-14 but rather it apparently prevents the A A isomerization resulting in the accumulation of A containing sterols in treated cells (3). 

In this report we will limit our discussion of chemical structure and biological activity to substituted pyridine and pyrimidine methanols which have been shown or are believed to inhibit demethylation at carbon 14, an action which leads to inhibition of demethylation, also at carbon 4. 

The 14c<-demethylation of dihydrolanosterol proceeds in three main stages with the two intermediates - the alcohol/ 5o -lanost-8-ene- 3p, 32-diol/ and the aldehyde/ 3p-hydroxy-5iX -lanost-8-en-32-al/ being tightly protein bound. The cytochrome P-450 is the component of the enzyme system required to initiate oxidation of the 14oC"itiethyl group/ but not of that responsible for the subsequent oxidation steps required for its elimination as formic acid (4). This initial oxidation also seems to be directly inhibited by the alcohol and aldehyde metabolities. 

Cameron, E.E., Bachman, K.E., Myohanen, S., Herman, J.G. and Baylin, S.B. (1999) Synergy of demethylation and histone deacetylase inhibition in the reexpression of genes silenced in cancer. Nature Genetics, 21, 103-107. 

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