Lecture 5: Basic Mechanisms of Toxicants 3 (NOT FINISHED

What are 2 days that you can get indirect generation of ROS/RNS?

1. Increased Ca2+ 2. Induction of CYPs

What are 4 mechanisms that cause the direct generation of ROS/RNS?

1. Xenobiotic bioactivation 2. Redox recycling 3. Transition metals 4. Inhibition of mitochondrial electron transport

ROS/RNS oxidatively inactivates ______________ and elevates Ca2+.

Ca2+/ATPases

ROS can disrupt _____________ membranes and dissipate the electrochemical gradient needed for ATP synthase.

Mitochondrial

____________ can cause changes to cell DNA that are passed on when cell divides, if this produces a neoplastic cell the agent is termed a _____________.

Mutagens; carcinogen

Hydrogen peroxide reacts with metals to produce ___________ __________.

Hydroxyl radicals

Tumor-suppressor genes ____________ cell cycle progression.

Inhibit

CYP enzymes are primarily found in the ___________.

Liver

Peroxynitrite reacts with carbon dioxide and creates __________ ___________ and a ___________ ________ radical.

Nitrogen dioxide; carbonate anion

____________ ______ is the imbalance of cellular oxidants and antioxidants in favor of oxidants.

Oxidative stress

ROS can directly ________ and affect protein function and can _________ DNA leading to cellular dysfunction.

Oxidize; mutate

What does ROS/RNS stand for?

Reactive oxygen species / reactive nitrogen species

ROS and RNS drain ATP ____________.

Reserves

NO is a ___________ inhibitor of cytochrome oxidase.

Reversible

What is the term for the creation of birth defects during fetal development?

Teratogenesis

What is the term for substances that induce birth defects?

Teratogens

Lipid Peroxidation Step 3: Lipid hydro peroxide (LOOH) is then formed by hydrogen _______________ from another lipid.

Abstraction

Nongenotoxic carcinogen does not cause ___________ ___________.

Cell death

Nongenotoxic carcinogen causes ____ ___________ and _________ ____________.

DNA replication; clonal expansion

Lipid Peroxidation Step 1: Free radicals can initiate perixidative _____________ of lipids by hydrogen abstraction from ________ _______.

Degradation; fatty acids

Proto-oncogenes ___________ cell cycle progression.

Promote

What two major classes of genes are involved in carcinogenesis?

Proto-oncogenes and tumor-suppressor genes

Neurons and endothelial cells constitutively express NOS that is activated by Ca2+ increased NO production which reacts with O2- to produce highly ___________ ONOO- .

Reactive

Lipid Peroxidation Step 2: The lipid radical (L.) formed is ______________ to the lipid peroxyl radical (LOO.) by oxygen ___________.

converted; fixation

Ca2+ - activated proteases convert xanthine _____________ to Xanthine ____________, the by-products of which are O2- and H2O2.

dehydrogenase; oxidase

Increased Ca2+ activates _____________ in citric acid cycle and increases __________ output (NADH and FADH2), which leads to an increase O2- (superoxide) by the e-transport chain.

dehydrogenases; electron

ONOO- ____________ activates complexes I/II/III and aconitase.

irreversibly