T&H 4 Chemical Carcinogenesis Flashcards
Name three direct-acting carcinogens.
- Nitrogen mustard
- Dimethylcarbamoyl chloride
- Beta-propiolactone
Name three procarcinogens that require metabolic activation to become carcinogenic. Which one is both a tumor initiator and tumor promoter?
- Polycyclic aromatic hydrocarbons
- Benzo(a)pyrene (BaP) - Aromatic amines
- Beta-naphthylamine (BetaNA) - Nitrosamines
- Diethylnitrosamine (DEN) - BOTH
What are examples of tumor promoting agents (non-genotoxic)?
- phenobarbital
- TCDD
- TPA
What is an example of a phase I enzyme?
Cytochrome P450 (CYP)
Name 5 phase II enzymes.
- glutathione-S-transferases (GSTs)
- uridine diphosphate (UDP)
- glucuronosyltransferases (UGTs)
- sulfotransferases (SULTs)
- N-acetyltansferases (NAT)
Name the 2 most common types of cellular damage induced by carcinogens.
- covalent adduct of carcinogen
- oxidative damage
_______ is a very sensitive marker of overall oxidative DNA damage.
8-oxo-deoxyguanosine
______ is often mistakenly substituted by DNA polymerase when DNA damage is not repaired by next cycle.
adenine
What does gamma-H2AX indicate?
indirect measure of DNA damage (DSBs)
Acute inflammatory response can lead to necrotic death. Dead cell products, such as _______, can trigger macrophages to release pro-inflammatory cytokines (_____ and _____) and ________, which causes respiratory burst. Name a signaling transduction pathway that is activated to drive expression of genes whose products result in chronic inflammation?
- high mobility group box 1 (HMGB1)
- IL-6 and TNF-alpha
- NADPH oxidase
- NF-kB
______ is the most widely used mutagenesis pathway. It uses what strain of bacteria that is mutated to prevent self-synthesizing of _______? What is another property of this strain of bacteria?
- Ames test
- Salmonella typhimurium
- histidine
- Salmonella that expresses recombinant human drug-metabolizing enzymes can be used (or just add a product)
What are the 5 overlapping models of carcinogenesis?
- Mutational
- Genomic instability
- Non-genotoxic clonal expansion
- Cell selection
- Microenvironment
Hepatic oxidation mediated by the CYP450 superfamily plays the greatest overall role in drug metabolism among phase I reactions – _____ is the predominant enzyme.
CYP3A4
CYP450 are most abundantly expressed in the _____ but are also expressed where else?
- liver most abundant
- kidney, lung, GI tract
What medications inhibit CYP450?
- Ketoconazole
- omeprazole
- fluoxetine
- cimetidine
What medications induce CYP450?
- Phenobarbital
- rifampin
- glucocorticoids
What 3 types of reactions are involved in phase I reactions?
oxidative (most important), hydrolytic, and reductive
_______ reactions produce metabolites that retain therapeutic activity or convert an inactive prodrug to an active moiety
phase I
What is the most commonly encountered phase II reaction?
Glucuronide conjugation catalyzed by uridine diphosphate glucuronosyl-transferases (UGT)
______ reactions are conjugating reactions that couple endogenous molecules to the parent drug or precursory phase I metabolite.
phase II
______ reactions produces inactive metabolites that can be eliminated from the body by biliary or renal excretion
phase II
Are phase I or phase II reactions considered a detoxification mechanism?
phase II
Cats lack what phase II enzymes? Which enzyme leads to their inability to glucuronidate acetaminophen and propofol?
- UGT: unable to glucuronidate acetaminophen and propofol
- NAT2 and TMPT
What phase II reaction are dogs incapable of due to deficiency in the enzyme family responsible for the reaction?
N-acetylation
What tumors have been linked to FIV infection?
- LSA
- SCC
- Mammary carcinoma
- Myeloproliferative disease
- histiocytic mast cell disease
- fibrosarcoma
