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