chemical toxicology flashcards

lol i love feeling weird

non polar groups

• lipophilic (fat loving)

• hydrophobic

• soluble in np solvents including fats

assessing lipophilicity

• kow = conc of solute in octanol/water 

• kow > 5000 or log10kow > 3.7 = molecule is likely to bioconcentrate (membrane permeable)

• negative kow = higher affinity for water 

benzene logkow

2.13

napthalene logkow

3.37

anthracene logkow

4.5

phenanthrene logkow

4.5

pyrene logkow

4.88 

benzo(a)pyrene logkow

6.1

benzo(e)pyrene logkow

6.2

chlorinated/brominated molecules

• very lipophilic/persistent 

• increase london disp forces 

• phenol (1.49)→ pcp (logkow 5.12)

• biphenyl (4.01)→ pcb (logkow 5.82)

hydrophilic substances

• water loving 

• polar groups such as -oh, -nh2, co2h

• soluble in water

• not readily taken up in gut, excreted in urine

london dispersion

instant dp induced attactions that occur btwn all molecules even non polar

dipole dipole interactions

instant dp induced attractions that occur btwn all molecules even non polar, stronger than disp forces

pi stacking interactions

pi pi stacking

• attractive noncovalent interactions btwn aromatic rings as they contain pi bongs 

• sandwich, tshaped, parallel displaced 

h bonding

dp dp attraction when h is covalently bonded to highly electronegative atom

• f > o > n

boiling point trends

• group iv = no hbond, increase due to molecules getting larger w more electrons

• h20/hf = more heat energy needed to break = hbond

prozac

• hbond acceptor/donor

• pi stacking

hydroxybenzoic acid derivative example

• weaker = pi stacking

• stronger = intermolecular hbond

alcohol (p) + alkyl halide (np)

ether (lp) + hbr

alcohol (p) + carboxylic acid (p)

ester (lp) + h2o

alcohol (p) + aldehyde (lp)

carboxylic acid (p)

functional group conversions

morphine → heroin (oh to ester)

bronsted-lowry acid

proton donor (h+)

bronsted-lowry base

proton acceptor (h+)

heterolytic bond cleavage 

RH → R- + (H+) proton
RH → R+ + (H-) hydride

homolytic bond cleavage

RH → Radical + (H) h atom

ph scale

basic/neutral for solution

acid dissociation - ka

ka = h3o+a-/ha

• stronger aid = more h30 = larger ka

strong acid pka value

small positive or negative

weak acid pka value

large pka value

weak acid examples

• carboxylic acid: rco2h pka = logkA

• water (10)

• phenol (15.7)

• ethanol (16)

organic base

amines

• ammonium ion → ammonia (conj acid → conj base)

surfactant

surface active agent

• amphiphilic structure 

• np/p 

anionic surfactant

• negative charge

cationic surfactant

• positive charge

amphoteric surfactant

• positive/negative charge

nonionic surfactant

• no charge

surfactant behavior

• hydrophobic group distorts structure of water

• some molecules expelled to surface of system w hydrophobic groups 

micelle formation: polar solvent

monomers → spherical micelles → cylindrical micelles → bilayer lamella

micelle formation: non polar solvent

monomer → reverse micelles → inverted hexagonal phase

soaps/detergents

saponification

triglyceride → sodium salt + glycerol, glycerin 

bio surfactants: bile salts

• aids with digestion to emulsify lipids

• bile salt accumulation = acutely toxic

acid/base properties of xenobiotics

• uncharged = more lipophilic, easily taken up from gi tract

• carboxylic acid/phenols = acid conj uncharged, basic conj ionic

• nitrogen base = acidic cong ionic, basic conj uncharged

• pka = acidity of toxicant 

oral cavity pka

6.8 -7.5

stomach cavity

1.5-2.0

duodenum pka

5.8-8.0

small intestine pka

7.2-7.5

colon pka

7.9-8.5

covalent binding interactions

activated drug + target dna/protein/etc → adduct

• adduct (addition product formation) can occur when drug is highly reactive (electrophile) and can covalently react w nucleophilic sites on target

nucleophiles

• electron rich molecules that have one unshared pair of electrons, negatively charged

electrophiles 

• accepts electrons as they are lacking an e 

4 key factors that contribute to nucleophilicity

1. charge: conj base better nucleophile (nucleophilicity inc w inc electron density)

2. electronegativity: nucleophilicity increases with decreasing electronegativity  (les er, less held electrons are)

3. solvent 

   1. polar protic (water): can h bond creating a shell of solvent molecules, nucleophile: less reactive as lp interacts with h atoms  of solvent

   2. aprotic: lack hbond, nucleophilicty increases going up periodic table (f(strongest)>cl>br>i)

4. steric hindrance: bulkiness

reactive intermediates

electrophiles 

1. carbon/nitrogen atoms attached to leaving group X (weak bases)

• results in bond polarization, nucleophile drawn to partially positive c atom\

• sn2 = one bond broken/one formed in one step (nucleophilic substitution)

2. carbocations (3>2>1>methyl)

• sn1 = nucleophile replacing leaving group, unimolecular and rate of rxn depends on concentration of one reactant (2 step)

3. carbonyl compounds

4. alpha,beta-unsaturated carbonyl compounds 

5. quinones: unique class of carbonyl compounds  

6. epoxides

• all reactions involve nucleophilic attack at carbon and lead to opening of ring

• driving force = steric strain 

question

• (-) gain e (anion)

• (+) lose e (cation)

radicals

have one unpaired e + v reactive

radical reactions

1. addition (r. +ch2=ch2 → rch2ch2.)

2. hydrogen abstraction (r. +LH → RH + L.)

3. electron abstraction (r. +ArNH→r- +ArNH+.)

4. termination (r.+y.→r-y)

5. disproportionation (ch3ch2r+ch3ch2r =ch3ch3 + ch2=ch2)

oxidative stress

• excess of prooxidant/antioxidant reactive species 

  • detrimental consequences (cancer/aging)

• results from exposure to ros 

• antioxidants combat oxidative stress

oxidative defense

small molecules

• water soluble: glutathione, uric acid, ascorbate

• lipid soluble: alpha-tocopherol, beta-carotene, coenzyme q

proteins 

• intracellular: sod 1/2, glutathione peroxidase, catalase

• cell membrane: sod 2, exGPX, plasma proteins

• extracellular: phospholipid hydroperoxide GPx

metabolism

• allows for enzymatic conversion of chemicals to polar compounds which are easily excreted

• most metabolites = water soluble due to addition of hydrophilic func groups

• more ionized than parent @ phys ph

• rendered less biologically active/inactivated

alcohol toxicology

ethanol (alcohol dehydrogenase) → acetaldehyde

acetaldehyde (aldehyde dehydrogenase) → acetic acid

95%, 5% in urine/feces/breath/sweat 

therapeutic agents & metabolism

• need to be metabolized to be active 

  • proximate carcinogens (parent not carcinogenic)

  • render more polar → concert to highly reactive electrophiles 

  • liver = xenobiotic metabolism primary site, largest concentration of metabolic enzymes 

  • first pass effect: pass through liver before target site (activated/inactivated)

phase 1 metabolism summary

cytochrome p450 

• types of reactions: hydrolysis, oxidation,reduction

• small inc in polarity

• exposes functional group

• can result in metabolic activation

phase 2 metabolism summary

conjugation pathways

• type of reaction: conjugation

• large inc in polarity 

• polar compound added to functional group 

• facilitates excretion 

cytochrome p450

• enzyme family responsible for biotransformation rxn used to metabolize endo/exogenous compounds 

• microsomal resulting from fragmentation of endoplasmic reticiulm

• mixed functional oxidases/monooxygenase because they catalyze insertion of one molecule of oxygen into substrate, one o atom is inserted into chemical and other is reduced to form h2o

• spectral properties 

  • when reduced to ferrous can bind ligands like o2/co

  • cyp450 absorbs light maximally @ 450 nm due to 5th ligand to the heme

cytochrome p450 oxygen rebound mechanism

cytochrome p450 - ppc hydroxylase

-oh replace -h

ch bond dissociation energy

1: 410 kj/mol

2: 395

3: 380

epoxidation of olefins

• undergo ring opening through reactions w nucleophiles

N-alkyl oxidation

ch2=o + h-r

oxycodone p450 metabolism

phase 2 metabolism

• couples metabolite w endogenous substrate resulting in large inc in metabolite polarity

  • increased metabolite stability 

  • eliminate reactive intermediates

phase 2 reactions conjugation

1. glucuronic acid - glucuronides

2. acetyl coenzyme a - acetylated 

3. paps - sulfonated 

4. glutathione - mercapturic acid 

glucuronidation

nucleophile (roh)

UDPGA cofactor

UDP-glucuronosyl transferase (ugt)

N-acetylation

nucleophile (rnh2)

acetyl-coa cofactor

N-acetyl-transferase (nat)

sulfation

nucleophile (roh)
paps cofactor

sulfotransferase (sult)

glutathione conjugation

electrophile (epoxide)
gsh cofactor

glutathione s-transferase (gst)

udp-glucuronosyltransferases

aglycone + UDPGA → glucuronide + UDP

• glucuronic acid = main sugar used to prevent accumulation of waste products of metabolism and fat soluble chemicals from the environment 

• UDPGT 

glucuronide structures

o-glucuronides 

heme catabolism

heme → biliverdin (heme oxygease)
biliverdin → bilirubin (nadph + h+ → nadp+)

bilirubin → bilirubin diglucuronide (UDPGT)

sulfotransferase

R-OH + PAPS → R-OSO3- + PAP

• SULFURIC ACID ESTERS

acetyl coa: NAT

substrates

• aromatic amines ar-nh2

• aromatic hydrazines ar-nh-nh2

• drugs: isoniazid, sulfamethazine, procainamide

• Synthetic intermediates: benzidine

• Food pyrolysis product heterocyclic amines

gsh - glutathione gamma-glutamylcysteinylglycine

• gamma peptide linkage prevents hydrolysis by peptidases 

  • ionized thiolate (gs-) is a good nucleophile

  • sulfur to donate e makes gsh good reductant

• GSH → GS- + H+ (pKA: 9.2)

• gsh as a reducing agent and free radical scavenger: defense against oxidative stress

• gsh reacts w many electrophiles to form covalent adducts

gsh as nucleophile

toxicant →(gsh-gsx adduct = stops toxicant) reactive metabolite (electrophile) → biological target (nucleophile) & macromolecule (dna/rna/protein) → covalent adduct → biological damage 

HPLC W MS LCMS

• high pressure liquid chromatography w mass spectrometry detection lcms

  • understanding activity/safety of key metabolites critical to overall evaluation of drug product 

mobile/stationary phase

mobile/stationary phase make contacty in interface set up

• affinity varies w solute 

• separation occurs due to differences in speed of motion

column and planar chromatography

LC to HPLC

• higher degree of separation 

• reduction of analysis time

  • eluent by pump

gradient system

isocratic system 

• constant eluent composition 

• long analysis time + poor separation

gradient system 

• varying eluent system (HPGE/LPGE)

• eluent comp changed gradually 

reversed phase chromatography

stationary phase: low polarity

• ods

mobile phase 

• high polarity 

• water/methanol/acetonitrile/salt sometimes added

separation column for reverse phase chromatography

eluent used in reversed phase mode

water + water soluble organic buffer

ratio has greatest influence on separation, ph is important separation parameter 

pH of eluent/retention of ionic solutes

normal phase: most non polar first (stationary: polar, mobile: np)

reverse phase: most polar first (stationary: np, mobile: polar)

HPLC DETECTORS

mass spec lcms

base peak = most intense peal 

ms parent ion = mwt of compound 

lcms advantages

can be id’d w ms spectra & quantitve analysis w excellent selectivity

detection limit

minimum quantity of target substance that can be detected

evaluation method 

• calculated from sd of measurements and slope of calibration curve 

acetaminophen

• hepatotoxicty = most common cause of acute liver failure