# Synergistic toxicity of reactive oxygen species

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $299,967

## Abstract

Hydrogen peroxide is a bio-specific toxin, inert with common organic or inorganic molecules,
but in sufficient concentrations killing any type of cells almost on contact, using cellular iron
to produce highly-reactive oxidizing species (Fenton's reaction). Chromosomal DNA is the
main cellular target of HP poisoning, although the nature of lethal chromosomal damage is
still unknown. Even more confusingly, HP turns out to be a surprising choice for a bio-
weapon, as the killing concentrations are 1,000-fold higher than the physiological ones,
while accumulation of HP in a particular cellular compartment is problematic, because its
small size and uncharged nature facilitates diffusion through membranes. Yet, our immune
cells somehow use these much lower HP concentrations to efficiently kill invading microbes,
by unclear mechanisms. Remarkably, HP toxicity is synergized by other simple molecules, like
nitric oxide (NO) or cyanide (CN). We hypothesize that our immune cells use otherwise
insufficient HP concentrations to kill bacteria by accumulating potentiator molecules (for
example, NO) in the compartments where high [HP] does not accumulate. However, the
metabolic mechanisms behind potentiated HP toxicity, thought to elevate the intracellular
free iron, are inconsistent with the newest results, while the mechanisms of irreparable
chromosomal damage remain mostly unclear. Our recent studies of HP+CN co-toxicity
uncovered new aspects of the phenomenon, like iron recruitment from intracellular depots
directly to DNA, or catastrophic chromosome fragmentation, which is responsible for the cell
killing. We propose to study HP+NO co-toxicity with three specific aims: 1) the nature of this
synergistic toxicity and the targets of NO action; 2) the DNA mechanisms behind the
catastrophic chromosomal fragmentation; 3) hunger shock as a metabolic potentiator of HP
toxicity. The major difference of our approach from the previous work is the emphasis on
DNA and chromosome damage, on the significantly expanded genetic scope and on testing
specific ways to enhance Fenton. Our long-term goals in this project are to understand the
mechanisms behind the catastrophic chromosome fragmentation on the one hand, and those
responsible for potentiation of HP toxicity on the other.

## Key facts

- **NIH application ID:** 9971283
- **Project number:** 1R01GM132484-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Andrei Kuzminov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $299,967
- **Award type:** 1
- **Project period:** 2020-03-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971283

## Citation

> US National Institutes of Health, RePORTER application 9971283, Synergistic toxicity of reactive oxygen species (1R01GM132484-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971283. Licensed CC0.

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