Captopril methylation in human liver and kidney: interindividual variability

Abstract

1. The methylation of captopril was studied in the microsomal fraction obtained from 87 specimens of human liver and 70 specimens of human renal cortex. 2. The rate captopril methylation ranged over one order of magnitude in the liver and kidney. In the human liver, the mean (+/- SD) rate of captopril methylation (pmol/min/mg) was significantly (p < 0.001) greater in women (199 +/- 97) than in men (126 +/- 88), whereas in the kidney no sex-difference was observed, and the mean (+/- SD) of all cases was 47 +/- 23 pmol/min/mg. 3. In the kidney, the statistical analysis revealed the presence of two subgroups in the rate of captopril methylation and their mean (+/- SD) estimates were 42.5 +/- 13.9 and 90.3 +/- 12.0 pmol/min/mg (p < 0.05). Of the population, 84% fell in the former and the remaining 16% in the latter subgroup. 4. Captopril is mainly eliminated by metabolism and its bioavailability is 65%. Methylation is one of the metabolic routes of captopril and its variability may contribute, to some extent, to modulate the intracellular concentration of this drug.

Metabolism of [6]‐shogaol in mice and in cancer cells

“…Initial conjugation with GSH promoted by glutathione transferase gives rise to the corresponding conjugate, and the GSH conjugate undergoes further enzymatic modification: first modification by ␥-glutamyltranspeptidase to form the cysteinylglycine conjugate; then alteration by cysteinyl-glycine dipeptidase or aminopeptidase M to form the cysteine conjugate; and finally conversion by N-acetyltransferase to form the N-acetylcysteine conjugate (Knapen et al, 1999). Then, both the cysteine and the N-acetylcysteine conjugates act as substrates of cysteine S-conjugate ␤-lyase, a mainly renal and hepatic enzyme that cleaves the S-C bond in the cysteinyl moiety, thus liberating a thiolated metabolite, which can be further S-methylated by thiol Smethyltransferase to form 5-methylthio-1-(4Ј-hydroxy-3Ј-methoxyphenyl)-decan-3-one (M10) or 5-methylthio-1-(4Ј-hydroxy-3Ј-methoxyphenyl)-decan-3-ol (M12) (Ferroni et al, 1996;Kishida et al, 2001).…”

Metabolism of [6]-Shogaol in Mice and in Cancer Cells

“…Initial conjugation with GSH promoted by glutathione transferase gives rise to the corresponding conjugate, and the GSH conjugate undergoes further enzymatic modification: first modification by ␥-glutamyltranspeptidase to form the cysteinylglycine conjugate; then alteration by cysteinyl-glycine dipeptidase or dmd.aspetjournals.org aminopeptidase M to form the cysteine conjugate; and finally conversion by N-acetyltransferase to form the N-acetylcysteine conjugate (Knapen et al, 1999). Then, both the cysteine and the N-acetylcysteine conjugates act as substrates of cysteine S-conjugate ␤-lyase, a mainly renal and hepatic enzyme that cleaves the S-C bond in the cysteinyl moiety, thus liberating a thiolated metabolite, which can be further S-methylated by thiol Smethyltransferase to form 5-methylthio-1-(4Ј-hydroxy-3Ј-methoxyphenyl)-decan-3-one (M10) or 5-methylthio-1-(4Ј-hydroxy-3Ј-methoxyphenyl)-decan-3-ol (M12) (Ferroni et al, 1996;Kishida et al, 2001). Electrophiles in foods have attracted great attention because of their protection against toxicity and many chronic pathological conditions (Nakamura and Miyoshi, 2010).…”

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. I. ROLE OF CYTOCHROME P450, METHYLTRANSFERASES, FLAVIN MONOOXYGENASES, AND ESTERASES

“…In humans, there are at least two methyltransferases, TMT and thiopurine methyltransferase (TPMT), that are capable of catalyzing the S-methylation of xenobiotic compounds (Weinshilboum et al, 1978(Weinshilboum et al, , 1979. TMT is primarily a membrane-associated enzyme and has been reported to catalyze the methylation of captopril (Keith et al, 1984;Ferroni et al, 1996), N-acetylcysteine and 7␣-thio-spirolactone (Keith et al, 1984), and diethyldithiocarbamate (Glauser et al, 1993a). TPMT is a cytoplasmic enzyme with a substrate preference for thiopurines, thiopyrimidines, and aromatic sulfhydryl compounds (Remy, 1963;.…”