Toxicology of antimicrobial drug

what is the danger of UV light

• UV light damages DNA, protein, lipids and cells

• Acute exposure leads to sunburn via an inflammatory response in the skin

• Chronic exposure can lead to skin cancer via DNA damage

• phototoxicity enhances sunburn → some medicines can increase this due to a molecule being activated by sunlight

how does sun tan and burn occur

• the UV light from the sun stimulates your skin to produce melanin

• this is the natural defence against sunlight → makes your skin darker

how does sun damage occur

• UV light breaks the bonds between DNA bases (left side)→ bases reform in different ways → rings form a tricyclic structure (right side)

• when we’re young, we are good at repairing this DNA damage

• body responds to this DNA damage by apoptosis (programmed cell death)

• when sufficient cells die, the skin will peel away

• repeated exposure makes it harder to repair → cancer 

how does the production of reactive oxygen species cause toxicity

• UV light exposure to oxygen → superoxide radical → hydrogen peroxide → free hydroxyl radical

• hydroxyl radical has an unpaired electron, which is really toxic in a cellular environment → oxidative stress as it wants its electron paired → reacts with our DNA, RNA, proteins and lipids in an uncontrolled fashion

• body responds by telling cells to die by apoptosis → damage to skin

how do tetracycline antibiotics cause phototoxicity

by redox cycling and toxicity 

• chemicals that undergo redox reactions are known as redox cyclers → tetracycline

• tetracycline produces superoxide, O₂^-  → excess superoxide, O₂^-  leads to oxidative stress → apoptosis → skin phototoxicity 

what is quinone redox cycling and how does this lead to toxicity 

• Drugs that contain a quinone moiety can be reduced to a semi-quinone

• semi-quinone can then be re-oxidised to the quinone (oxygen is reduced)

• this second process releases superoxide (electron is released)

• molecule has an unpaired electron, which is toxic in the cellular environment

• wants to pair by reacting with DNA, proteins and lipids

• cells die by apoptosis

Other quinone-type species can behave in a similar way

why does phototoxicity increase in these tetracyclines

• minocycline doesn’t contain the quinone moiety when it gets oxidised

• doxycycline and demeclocycline contain the quinone moiety → can go through redox cycling and cause toxicity

  • doxycycline contains one quinone-like carbonyl group

  • demeclocycline contains two quinone-like carbonyl groups → better redox cycler

• superoxide, O₂^-  produced  → excess superoxide, O₂^-  leads to oxidative stress → apoptosis → skin phototoxicity 

do you think phototoxicity or photoallergy is more of a concern 

Phototoxicity

• as it is generally related to the dose and UV exposure.

• It is more widespread as it does not rely on the immune system for a response.

• It also enhances the risk from sunburn

What types of patients are more at risk from phototoxicity?

• fair skin, freckles etc

• Patients who use sunbeds

• elderly 

• those who work outside