Thiol-Containing Drugs

Clinical use Chemical name Proprietary or trivial name(s) 

---

Methyl groups from SAM are also transferred to thiol-containing drugs and xeno-biotics. It appears that the only structural requirements are the presence of a free thiol and that the compound is not too hydrophilic in nature. S-Methylation has been demonstrated with mercaptoethanol, thioacetanilide, and 6-mercaptopurine, as well as with a variety of thiopurine and thiopyrimidine drugs. In general, aromatic thiols are the best substrates, while simple aliphatic thiols are less active. 

Thiol-containing drug.s. such as propylthiouracil, 2, 3-dimcrcapto-1-propanol (BAL). and 6-mcrcaptopur-ine. " al.so have been reported to undergo S-mcthylation. 

Free thiol groups react with cysteinyl-disulfide residues in proteins to form a new disulfide link with the concomitant release of a free cysteine residue within the protein (Scheme 12, pathway A). No metabolic activation is required for the covalent binding process to occur. Thiols are also readily oxidized to sulfenic acids, which react with cysteinyl residues and reduced GSH to form mixed disulfides (Scheme 12, pathway B) (Migdalof et al., 1984 Coleman et al., 1988). Methimazole, penicillamine, and captopril are examples of free thiol-containing drugs wherein evidence has been presented that traces toxicity of these compounds with oxidation of the thiol group. 

Table 5.2 Naturally occurring thiols and some thiol containing drugs...

Most thiols and thiol-containing drugs oxidise in solutions, such as physiological fluids, at neutral pH. Careful sample preparation is thus essential to ensure that the measurement accurately reflects true thiol concentrations. 

All reduced thiols contain very active SH groups and therefore, are potentially efficient antioxidants. There are numerous endogenous and synthetic thiols, which have already been studied and applied as antioxidative drugs and food supplements, but the most important antioxidant thiols are undoubtedly lipoic acid and glutathione. 

Thiol S-methyltransferase is a microsomal enzyme found in the liver, lung, and kidney, which will catalyze the methylation of a wide variety of foreign compounds. A number of sulfur-containing drugs such as disulfiram, D-penicillamine, and 6-mercaptopurine are methylated in humans by thiol S-methyltransferase or thiopurine methyltransferase. Methylation of the anticancer drug thiopurine by the latter enzyme is a detoxication reaction, reducing the myelotoxicity of the drug (see Fig. 4.18, which shows the reverse of this reaction). 

Glutathione (23 in Figure 32.1 IGSH) is a thiol-containing tripeptide of major significance in the detoxification and toxification of drugs and other xenobiotics. In the body, it exists in a redox equilibrium between the reduced form (GSH) and an oxidized form (GS-SG). The metabolism of... 

S-Methylation is also an important pathway in the biotransformation of many sulfur-containing drugs. At least two separate enzymes, thiol methyltrans-ferase (TMT) and thiopurine methyltransferase (TPMT) are known to catalyze S-methylation in humans [87], TMT, a membrane-bound enzyme, catalyzes the S-methylation of captopril, D-penicillamine, and other aliphatic sulfhydryl compounds such as 2-mercaptoethanol. On the other hand TPMT, a cytosolic enzyme, catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds including 6-mercaptopurine and other thiopurines. Recently, S-methyltransferase has been shown to play a critical role in the metabolism of the antipsychotic drug, ziprasi-done, in humans [72, 88]. Both TPMT and TMT have been shown to be genetically polymorphic in humans. 

Qiu, B., Stefanos, S., Ma, J., Lallo, A., Perry, B. A., Leibowitz, M. J., Sinko, P. J. and Stein, S., A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene glycol)-based copolymer a new biomaterial for protein drug delivery. Biomaterials, 24,11, 2003). 

---