Biochemical studies of toxic agents. The metabolism of 1- and 2-bromopropane in rats

Abstract

1. (+)-n-Propylmercapturic acid sulphoxide, i.e. (+)-N-acetyl-S-n-propyl-l-cysteine S-oxide, was prepared as the dicyclohexylammonium salt, (-)-n-propyl-mercapturic acid sulphoxide was prepared as the free acid, and S-isopropyl-l-cysteine and isopropylmercapturic acid were also prepared. 2. The metabolism of 1- and 2-bromopropane was studied by radiochromatographic examination of the urine excreted by rats that had been fed with a diet containing (35)S-labelled yeast and then injected subcutaneously with these compounds. In addition to n-propyl-mercapturic acid and 2-hydroxypropylmercapturic acid, the excretion of which has already been reported, n-propylmercapturic acid sulphoxide was shown to be a metabolite of 1-bromopropane. Sulphur-containing metabolites of 2-bromopropane, if present in the urine at all, were there in very small amounts. 3. n-Propylmercapturic acid and isopropylmercapturic acid were isolated from the urine of rats that had been injected subcutaneously with S-n-propyl-l-cysteine and S-isopropyl-l-cysteine respectively.

The Role of Glutathione and Glutathione S‐Transferases in Mercapturic Acid Biosynthesis

“…West and Mathura (1954) showed that 12 arylcysteines were acetylated to the mercapturic acid in the rat. Acetylation of the cysteine derivative is the final stage in mercapturic acid biosynthesis and has been demonstrated in vivo and in vitro with liver homogenates or slices (Gutman and Wood, 1951;West, Mathura, and Black, 1951;Bray, Franklin, and James, 1959b;Thomson, Barnsley, and Young, 1963;Barnsley, Grenby, and Young, 1966).…”

“…Hydroxyalkylmercapturic acids could also be formed by hydroxylation of the corresponding alkylmercapturic acid or precursor before excretion, as rat liver slices convert S-butylcysteine and butylmercapturic acid to hydroxyalkylmercapturic acids (James, Jeff ery, Waring and Wood, 1968 Hydroxyalkylmercapturic acid formation is restricted to alkyl halides containing more than two carbon atoms since these hydroxyalkylmercapturic acids have not been reported as metabolites of iodomethane (Barnsley and Young, 1965) or bromoethane (Thomson et al, 1963). Bromoethane and 1-bromopropane (23) are also partly metabolized to the alkylmercapturic acid sulfoxide (Barnsley, Thomson, and Young, 1964;Barnsley, Grenby, and Young, 1966). The significance of this is unknown, but several S-alkyl-L-cysteine sulfoxides occur naturally in plants, e.g., alliin (28) in garlic (Virtanen, 1962).…”

NTP-CERHR Expert Panel report on the reproductive and developmental toxicity of 1-bromopropane

“…In vitro experiments with rat hepatic microsomes suggests there are multiple pathways for metabolism of 2-BP [19]. A study in rats tentatively demonstrates that 2-BP is not excreted in urine in the form of mercapturic acid or other sulfur containing conjugates [18]; however this study is limited due to the methodology available to the investigators and the panel does not have high confidence in its conclusions.…”

“…Barnsley et al [18] fed two male rats [age and strain unspecified] a diet containing 35 S-labelled yeast for 3 days, injected 2 of the rats subcutaneously with 0.7 ml of 40% w/v solution of 2-BP [purity not specified] in arachis oil on the fourth day, collected urine for 24 h following treatment, and measured metabolites in urine by radiochromatography. No significant levels of sulfur-containing metabolites were present in the urine at detectable levels.…”

Bromide and N-acetyl-S-(n-propyl)-l-cysteine in urine from workers exposed to 1-bromopropane solvents from vapor degreasing or adhesive manufacturing

“…1 that includes exhalation of unaltered 1-BP, debromination releasing free Br (-) ion, oxidation by CYP2E1, and S-conjugation with glutathione (Barnsley et al 1966;Walsh 1979, 1980;Garner et al 2006). An intermediate metabolite, S-n-propyl-glutathione, is cleaved to S-n-propyl-L-cysteine, which is metabolized producing several mercapturic acid conjugates excreted in urine.…”