Intestinal metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats: Sex difference, inducibility and inhibition by phenethylisothiocyanate.
The intestinal metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was investigated in male and female Sprague-Dawley (SD) rats and male F344 rats, using isolated perfused intestinal segments. [1(-14)C]-NNK at 1 microM was metabolized by alpha-hydroxylation, pyridine N-oxidation and carbonyl reduction. Jejunal segments from control female rats metabolized 26.2% of the NNK during transepithelial transfer to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, 12.2%), 4-(methylnitrosamino)-1-3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide, 7.7%), 4-oxo-4-(3-pyridyl)-butanol (KAlc, 2.7%), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol (NNAL-N-oxide, 1.8%), 4-oxo-4-(3-pyridyl)butyric acid (KA, 1.1%) and 4-hydroxy-4-(3-pyridyl)butyric acid (HA, 0.7%). Ileal segments metabolized 20.8% of the NNK during absorption, with no difference in metabolite distribution as compared to jejunal segments. In control male SD and F344 rats, jejunal presystemic metabolism was 2.3-fold higher (56.4% and 60.8% respectively), mainly because of a 4-fold increase in NNAL formation (44.1% and 48.5%)> total NNK metabolism was also induced in female rats by starvation (84.4% metabolites), acetone (89.3%), phenobarbital PB, 75.3%) and Clophen A50 (61%). PB and Clophen A50 induced N-oxidation to 38.9% (4 x) and 27.8% (3 x), and to a lesser extent NNAL formation and alpha-hydroxylation (2 x), Starvation mainly increased N-oxidation with a time-dependent increase from 1 day to 3 days of starvation (4 x and 8 x versus controls), whereas alpha-hydroxylation and NNAL formation was elevated only after 1 day starvation. Acetone pretreatment (3 days) stimulated all three pathways (NNAL 2 x, N-oxidation 4 x, alpha-hydroxylation 4 x). In male F344 rats, starvation and acetone induced N-oxidation (5 x and 7 x) and alpha-hydroxylation (3 x and 5 x), and decreased NNAL formation by 40%, probably due to substrate competition or further metabolism of NNAL. In acetone-induced female SD rats, NNK metabolism was inhibited by in vivo pretreatment with phenethylisothiocyanate (PEITC) or in vitro addition of 1% ethanol to the perfusate. Both inhibition experiments reduced total metabolism by 20%; N-oxidation and alpha-dhyroxylation were reduced to values found in control rats, whereas NNAL formation increased from 31% to 51%.Inhibition of NNK metabolism by PEITC im male F344 rats was less pronounced compared to female SD rats; again a decrease in alpha-hydroxylation (6.7% to 3.3%) and N-oxidation (73.6% to 35.3) was accompanied by increased NNAL formation (9.8% to 41.0%).(ABSTRACT TRUNCATED AT 400 WORDS)
Schulze
J
J
Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig Maximillians-Universität München, Germany.
Malone
A
A
Richter
E
E
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism*; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D009602:Nitrosamines / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013045:Species Specificity
D002273:Carcinogens; D017879:Isothiocyanates; D009602:Nitrosamines; D000096:Acetone; D000431:Ethanol; C058305:phenethyl isothiocyanate; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D010634:Phenobarbital