title: Flavin-containing monooxygenase-dependent stereoselective S-oxygenation and cytotoxicity of cysteine S-conjugates and mercapturates.
abstract: The metabolism of cysteine S-conjugates of both cis- and trans-1,3-dichloropropene in the presence of rat kidney microsomes and purified flavin-containing monooxygenase from hog liver was investigated in vitro. Preliminary studies with isolated rat kidney cells demonstrated that cysteine S-conjugates were quite toxic to the cells in a process which was consistent with a role of the flavin-containing monooxygenase in the bioactivation of the nephrotoxins. Putative S-oxide metabolites of cysteine S-conjugates were chemically synthesized, and diastereomers were separated and identified by spectroscopic means. The metabolic products of cysteine S-conjugates were identified by comparing the chemical properties of the metabolites with authentic synthetic cysteine S-conjugate S-oxides. Surprisingly, S-conjugate S-oxygenase activity was not observed with rat kidney microsomes but was present when cysteine S-conjugates were incubated with the highly purified flavin-containing monooxygenase from hog liver. The kinetic parameters indicated that considerable S-oxygenase stereoselectivity and structural selectivity was observed: cis cysteine S-conjugates were preferred substrates and N-acetylation of cysteine S-conjugates decreased substrate activity. S-Oxygenation was considerably diastereoselective and diastereoselectivity was much greater for cysteine S-conjugates with higher Vmax values. Cysteine S-conjugate S-oxides were not indefinitely stable, and under certain conditions, the S-oxides underwent a [2,3]-sigmatropic rearrangement to acrolein. Formation of acrolein or other electrophilic products from S-(chloropropenyl)cysteine conjugate S-oxides may contribute to the renal effects observed for S-(chloropropenyl)cysteine conjugates.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco.
authors.forename: S B
authors.initials: SB
authors.lastname: Park
authors.forename: J D
authors.initials: JD
authors.lastname: Osterloh
authors.forename: S
authors.initials: S
authors.lastname: Vamvakas
authors.forename: M
authors.initials: M
authors.lastname: Hashmi
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
authors.forename: J R
authors.initials: JR
authors.lastname: Cashman
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism
chemical_list: C075955:S-(3-chloro-2-propenyl)cysteine; C042828:N-acetyl-S-(3-chloroprop-2-enyl)cysteine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D003545:Cysteine; D000111:Acetylcysteine