Screening of 16 common therapeutic drugs. Possible association with the Ah locus

Y. T. Chen, S. W. Bigelow, R. C. Levitt, D. W. Nebert

Research output: Contribution to journalArticle

Abstract

16 common therapeutic agents were screened for differences in sedation or lethality between C57BL/6N and DBA/2N inbred mouse strains that had been previously treated with β-naphthoflavone. No differences were observed for meprobamate, valium, promethazine, valproic acid, lincomycin, imipramine, terbutaline, propoxyphene, nitrofurantoin, amphotericin B, or diphenhydramine. C57BL/6N mice appeared to be more resistant than DBA/2N mice to the lethal effects of isoxsuprine, niridazole, pentazocine, isoniazid, and hydralazine. None of these latter five drugs had any capacity to displace [3H-1,6]2,3,7,8-tetrachlorodibenzo-p-dioxin from the liver cytosolic Ah receptor in C57BL/6N mice. With the use of β-naphthoflavone-pretreated offspring from the (C57BL/6N) (DBA/2N)F1 X DBA/2N backcross, a strict correlation (100% of 24 individuals in each case) was found between the Ahb allele and resistance to the lethal effects of isoxsuprine or niridazole. No correlation between the Ah locus and pentazocine, hydralazine, or isoniazid lethality was apparent. These results indicate that presence of the Ahb allele is associated with increased protection against isoxsuprine and niridazolone lethality. This increased protection may reflect enhanced detoxication metabolic pathways (e.g., induced cytochrome P1-450 and/or uridine diphosphate glucuronosyltransferase controlled by the Ah locus). The increased protection is not related to interaction of these drugs with the Ah receptor. It should be kept in mind that gene-environment interactions involving the Ah locus and isoxsuprine or niridazole may be important in certain instances.

Original languageEnglish (US)
Pages (from-to)269-283
Number of pages15
JournalDevelopmental Pharmacology and Therapeutics
Volume6
Issue number4
DOIs
StatePublished - Jan 1 1983
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology (medical)

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