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Oxygen and redox-active drugs: shared toxicity sites
Abstract:
Paraquat and nitrofurantoin can accept single electrons and, under appropriate conditions in tissues and cells, can pass these electrons to oxygen, thus participating in redox cycling. Similarities in the response of the target organ (the lung) and in subsequent pathology have also been observed among animals poisoned by oxygen and by these chemicals. We report evidence primarily obtained from Escherichia coli for common biochemical sites of toxicity for these agents. Common sites for oxygen and paraquat involve biosynthesis of specific amino acids, induction of genetic stringency via unloaded tRNAs resulting from amino acid deficiencies, decreased thiamin content, and impaired biosynthesis of pyridine nucleotide coenzyme biosynthesis for paraquat and oxygen. Inhibition of specific amino acid biosynthesis and induction of stringency also have been observed for nitrofurantoin. RNA and DNA biosynthesis are also impaired by oxygen; this has not been examined for paraquat or nitrofurantoin. There is a biochemical basis and preliminary data to support inhibition of NAD biosynthesis as a component of mammalian toxicity for these agents. Niacin may act to circumvent the consequences of the biochemical lesion at quinolinate phosphoribosyl transferase in NAD biosynthesis.
Insights
Paraquat and nitrofurantoin exhibit redox cycling, impacting cellular processes like amino acid and NAD biosynthesis. Niacin may mitigate toxicity by targeting NAD pathway enzymes.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Paraquat and nitrofurantoin undergo redox cycling, transferring electrons to oxygen.
- Similarities in lung pathology are observed in animals poisoned by oxygen and these chemicals.
Purpose of the Study:
- To identify common biochemical sites of toxicity for paraquat, nitrofurantoin, and oxygen.
- To investigate the role of NAD biosynthesis inhibition in mammalian toxicity.
Main Methods:
- Studies primarily conducted in Escherichia coli.
- Analysis of biochemical pathways including amino acid biosynthesis, genetic stringency, and coenzyme production.
Main Results:
- Common toxic mechanisms involve amino acid biosynthesis inhibition and genetic stringency induction.
- Paraquat and oxygen impair pyridine nucleotide coenzyme biosynthesis.
- Nitrofurantoin also inhibits amino acid biosynthesis and induces stringency.
Conclusions:
- Evidence supports common biochemical targets for paraquat, nitrofurantoin, and oxygen toxicity.
- Inhibition of NAD biosynthesis is a potential mechanism of mammalian toxicity for these agents.
- Niacin may offer a protective effect by influencing NAD biosynthesis.