Effects of long term dietary phenethyl isothiocyanate on the microsomal metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in F344 rats.

Phenethyl isothiocyanate (PEITC), a cruciferous vegetable component, inhibits lung tumor induction by the tobacco specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). To gain insight into the mechanism of PEITC lung tumor inhibition, we examined, in male F344 rats, the effects of dietary PEITC (3 micromol/g NIH-07 diet) in combination with NNK treatment (1.76 mg/kg, s.c., three times a week) for 4, 12 and 20 weeks on liver and lung microsomal metabolism of NNK and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of NNK and also a lung carcinogen. This was compared with rats fed NIH-07 diet, without PEITC, and treated with NNK alone or saline. The protocol was identical to that employed for inhibition of lung tumorigenesis by PEITC. We observed decreased rates of alpha-hydroxylation of NNK and NNAL in lung microsomes of 4-, 12- and 20-week PEITC + NNK treated rats compared with those treated with NNK or saline. NNK treatment alone also decreased lung alpha-methylene hydroxylation of NNK. Long-term NNK + PEITC administration did not significantly affect liver oxidative metabolism of NNK or NNAL, and did not affect the rate of glucuronidation of NNAL in liver microsomes when compared with rats treated with NNK or saline. Thus, PEITC selectively inhibited lung metabolic activation of NNK and NNAL. These results support the hypothesis that PEITC inhibits NNK-induced lung tumors by inhibiting metabolic activation of NNK in the lung. This study also demonstrated that PEITC inhibits lung alpha-hydroxylation of NNAL; this may play a role in PEITC inhibition of lung tumorigenesis by NNK.

Comparative metabolism of the tobacco-related carcinogens benzo[a]pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and N'- nitrosonornicotine in human hepatic microsomes.

We compared the metabolism in human hepatic microsomes of three tobacco smoke carcinogens believed to be involved in the induction of cancer in humans: benzo[a]pyrene (BaP),4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N'-nitrosonomicotine (NNN). The metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of NNK, was also investigated. Although the metabolism of some of these compounds by human enzymes or tissue preparations has been previously examined in some studies, they have never been compared in the same human hepatic samples. Moreover, there have been no previous reports of NNAL metabolism by human tissues or enzymes. The tritium-labeled carcinogens (3 microM) were incubated with 10 different human hepatic microsomal preparations and cofactors for 10-20 min, and the products were analyzed by radioflow HPLC. NNN was the best substrate for oxidative metabolism, with the 5'-hydroxylation pathway being the predominant one observed (mean +/- SD = 31 +/- 17 pmol/min/mg protein). alpha-Hydroxylation of NNK by the methylene and methyl hydroxylation metabolic activation pathways was the next fastest reaction, with rates of 3.1 +/- 1.9 and 3.3 +/- 1.1 pmol/min/mg protein, respectively. Metabolism of BaP resulted in the formation of dihydrodiols and phenols; trans-7,8-dihydro-7,8-dihydroxy-BaP, its major proximate carcinogen, was formed at a rate of 1.1 +/- 0.61 pmol/min/mg protein. alpha-Hydroxylation of NNAL proceeded at a rate of 0.53 +/- 0.26 pmol/min/mg protein. The results of this study demonstrate that human hepatic microsomes metabolize all of these tobacco carcinogens resulting in a substantial stream of electrophilic intermediates capable of binding to DNA. The relative rates of oxidative metabolism to electrophiles or their precursors were NNN > NNK > BaP > NNAL. Correlation studies indicated involvement of cytochrome P4502A6 in the 5'-hydroxylation of NNN and cytochrome P4503A4 in the alpha-methylene hydroxylation and pyridine-N-oxidation of NNK and NNAL. The results of this study provide the first data on the comparative metabolism of these important carcinogens in human hepatic microsomes.

Hypothesis-testing and nonlinguistic symbolic abilities in language-impaired children.

This study sought to clarify further the cognitive abilities of language-impaired children by examining their hypothesis-testing and nonlinguistic symbolic abilities. A discrimination learning task and a concept formation task were used to measure hypothesis-testing abilities, and a haptic (touch) recognition task was used to assess nonlinguistic symbolic abilities. Subjects were 10 language-impaired and 10 language-normal children matched for performance Mental Age. Measures of expressive and receptive language were also obtained from each child. The language-impaired children were found to perform significantly poorer than their MA controls on the haptic recognition task and on a portion of the discrimination learning task. No differences were found between the two groups' concept formation abilities. Correlational analyses revealed a particularly strong positive relationship between performance on the Peabody Picture Vocabulary Test and the haptic recognition tasks. It was speculated that this relationship was motivated by the symbolic demands of these tasks. One implication of this speculation is that a symbolic representational deficit might better explain the receptive language deficit than the expressive one.