Lack of detectable DNA alkylation for bromhexine in man.
It is known that in vitro incubation of the expectorant drug bromhexine (N-methyl-N-cyclohexyl-(2-amino-3,5-dibromobenzyl)-ammonium hydrochloride) with nitrite yields methylcyclohexyl nitrosamine (NMCA). NMCA is capable of methylating DNA when administered to rats. In vivo tests with bromhexine have also demonstrated that the drug methylates DNA when it is orally administered in the presence of sodium nitrite, presumably due to the intragastric formation of NMCA. In this study the potential of bromhexine to methylate nucleic acids in man, under physiological conditions, has been investigated. 20 volunteers were orally administered on each of three successive days 48 mg of bromhexine hydrochloride, labelled with three deuterium atoms in the N-methyl group. Urine was collected before treatment and subsequent to the last dose, and analysed by GC-MS for d0- and d3-7-methylguanine. 7-Methylguanine is naturally occurring in urine owing to the turnover of t-RNA of which it is a minor constituent. It is also a repair product from nucleic acids methylated by carcinogens, which is known to be excreted unmetabolised largely within 24 h of the methylation process. Unlabelled 7-methylguanine was present at levels of 7.36 +/- 2.43 mg/d in control urine and 6.12 +/- 2.36 mg/d in treated urine, in accord with previously published values. The excretion of isotopically labelled 7-methylguanine averaged 0.43 +/- 0.077% of the unlabelled concentration for control urines and 0.44 +/- 0.066% for treated urines, i.e. no d3-7-methylguanine could be detected following the drug treatment. The observed signals were largely accounted for by the naturally occurring isotopes 13C and 15N.(ABSTRACT TRUNCATED AT 250 WORDS)
Farmer
P B
PB
Medical Research Council (MRC), Toxicology Unit, Carshalton, Surrey, U.K.
Parry
A
A
Franke
H
H
Schmid
J
J
D000284:Administration, Oral; D000478:Alkylation; D001964:Bromhexine / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008745:Methylation
D006147:Guanine; C008450:7-methylguanine; D004247:DNA; D001964:Bromhexine