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Summary of all lectures Metabolism and Toxicology
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Summary of all lecture notes Metabolism and Toxicology
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Pharmacological versus teratogenic effectsNSAIDs (Nonsteroidal anti-inflammatory drugs) → not to be used during second half of pregnancy
• Reduced contractions
• Increased blood loss during birth
• Reduced foetal urine production → Potter sequence
➢ Amniotic fluid loss (oligohydramnios)
➢ Foetus compressed by uterus → TERATOGENIC EFFECTS: low-set ears; small
receding chin; beaklike nose; abnormally bent extremities (clump foot); pulmonary
hypoplasia.
Medication crucial for normal function of mother
e.g. anti-epileptics
• Increased incidence or birth defects (2-3 times, less than 10%)
• Medication evaluation preconception → can a ‘less’ teratogenic alternative be
used?
• Plasma levels change during pregnancy
• Can cause folic acid and vitamin-K deficiency (spina bifida, clotting disorders in
new-born)
Carcinogenesis and genotoxicity
Carcinogens → are agents that lead to:
• Increase in number of tumors of one or more types
• Unusual tumors
• Accelerated tumor formation (compared to untreated and natural incidence)
Neoplasm: heritably altered, relatively autonomous growth of tissue with abnormal regulation of
gene expression.
• Cancer is a malignant neoplasm
Benign → frequently exhibiting slow rates of proliferation that do not invade surrounding tissues
encapsulated - non-invasive - not metastatic - slow rates of proliferation (suffix -oma: fibroma,
adenoma...)
Malignant → invasive growth, capable of metastases to other tissues and organs
not encapsulated - invasive growth - metastatic (from epithelium: carcinoma; mesenchymal:
sarcoma. Ex: fibrosarcoma, osteosarcoma....)
A substance is a carcinogen (International Agency for Research on Cancer – IARC - definition) if it
induces malignant neoplasms.
Carcinogens:
• natural substances
• xenobiotics incl. drugs
• viruses
• radiation
NOTE: structurally very different substances with variable potency!
Genetic predisposition also matters:
• deficiency in repair
• deficiency in (de) toxification
• deficiency in apoptosis
,Classification of chemical carcinogens:
1: proven carcinogen in humans
2A: probably carcinogenic - positive in animal, likely in humans
2B: possibly carcinogenic - positive in animal, not enough data in humans
3: unknown = not classified, insufficient data
4: proven non-carcinogenic (almost impossible to prove!)
NOTE: Classification by means of epidemiological investigation and exposure of large groups of
people.
Carcinogens do all have very different structures!
The higher the capacity to bind to DNA → the higher the index of carcinogenicity
IACR class 1 carcinogens
Drugs:
• Tamoxifen (breast cancer) → endocrine disruptor
• Diethylstilboestrol (DES, hormone replacement therapy for menopause) → estrogenic
activity (also endocrine disruptor)
• Cyclosporine (immunosuppressant after organ transplantation) → inhibits immune system
• Chlorambucil (chemotherapy) → inhibitor of cell division, DNA damage
Others: Alcohol; Asbestos; Smoking
Genotoxic carcinogens: direct interaction with DNA, resulting in damage or change in structure of
DNA
• Mutagenic
• Can be complete carcinogens
• Tumorigenicity is dose responsive
• No theoretical threshold
Non-genotoxic (epigenetic) carcinogens are substances which are carcinogenic by changing DNA
expression without changing DNA structure or by making it more susceptible to DNA damage from
other sources
• Non-mutagenic
• Threshold, reversible
• Tumorigenicity is dose responsive
• May function at tumor promotion stage
• No direct DNA damages
• Species, strain, tissue specificity
Important: usually genes involved are oncogenes or tumor suppressor genes (see later)
Stages of carcinogenesis
Initiation → rapid, heritable, irreversible!
• Genotoxic carcinogen
• DNA modification
• Mutation, often multiple ones and in genes important for regulation of cell cycle
• If not repaired, one cell division necessary to lock-in mutation
• Modification is not enough to produce cancer
• Single treatment (exposure) can induce mutation. No safe treshold! (We are constantly
exposed to promotors!) → Carcinogen induced mutation
,Once initiated, different possible outcomes:
• Repaired!
• remains static / non-dividing
• dies (not compatible with viability or via apoptosis)
• Inititated cell proliferates! → stage 2: promotion
Promotion → clonal expansion of initiated cells: preneoplastic lesion (irreversible)
• Involves non-genotoxic (not mutagenic) carcinogens
• No direct DNA modification
• Acts via changes in gene expression leading to increased proliferation or decreased cell
death
• Multiple or prolonged treatment necessary!
• Multiple cell divisions necessary
Progression
• Changes from preneoplastic lesion to neoplasia (benign/malignant)
• DNA modification involved again: additional genotoxic event/s leading to chromosomal
aberrations and translocations
• Irreversible!
• Numbers of treatments needed with compound unknown (may require only single
treatment)
To develop to a tumor: application of an initiator and repeated exposure to a promotor (non-
genotoxic) is necessary!!!
• Order, frequency matter
2 different hypotheses on cancer initiation
1) Initiation in normal somatic, differentiated cell:
→ reprogrammed to less differentiated cell
→ immortalization: cells (re)gain ability to divide
2) Initiation into multipotent stem cell
→ loss of asymmetric division
→ preservation of immortalized state
→ block of differentiation
, Genotoxic agents: any chemical, physical and biological factors that cause permanent or reversible
changes in the genetic material
Direct acting carcinogens: highly reactive electrophilic molecules interacting with nucleophiles, such
as DNA → Typically leading to tumor formation directly at site of exposure!
Indirect acting genotoxic carinogens: become carcinogenic after metabolism → Tumor formation at
site of metabolic activation (not at exposure site)
Mutagenesis: DNA damage
Mutations = change of base pairs by deletion, addition, or transformation.
Clastogenesis: chromosome damage
DNA chains break and broken parts are joined together incorrectly or parts are lost.
Aneugenesis: change in chromosome number
Chromosomes are unequally distributed among the daughter cells during replication.
Causes of mutations
1. Alkylating electrophiles:
→ Directly interacting
→ After bioactivation
2. Radicals/ROS (typically leading to hydroxylation of
DNA):
→ Formed after bioactivation
→ Induced from radiations
3. Radiation (direct damage or via formation of radicals)
4. Incorporation of different base
5. Intercalating agents
For each nucleotide there are many different chemically reactive sites known, also the
phosphodiester backbone can be attacked!!!
1. Alkylating electrophiles
Perturbation of hydrogen bonds between the nucleotides of DNA → by electrophiles
• Can induce mutagenesis by an error in replication
C-G: 3 H-bonds
A-T: 2 H-bonds
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