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Do your reading, review your homework and lectures. For questions B and C, use reference
material and don’t be afraid to think outside the box. You may use the images in the Powerpoint
file (20.201 ’13 Question 2 Structures.pptx) to draw structures for your answers. Use PPT
drawing tools to decorate the images. Then select the image and its associated decorations, copy,
and paste in your Word document answer sheet as a PDF or JPEG image. Alternatively, submit
the PPT file with your answer document.
A. Hypo 1 was found to be toxic, so the chemists came up with Hypo 2. You have been
Hypoamericillin 2
OCH3
F
Hypoamericillin 1
OCH3
F
HO
O
HO
F
HO N N
S
OH
O
OH
N
O
O
OH
HN
asked to predict whether 2 will be more
or less toxic than 1, or about the same.
Ignore the changes in bond angles, it’s
my mistake. Back up your answer with
chemistry.
Including what you think is the most
important electrophile for each
structure.
B. In preclinical toxicity testing of
Diclofenac in Chinese Hamster Ovary
Cells containing the entire complement
of human cytochrome p450 metabolic
activity,
F
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the drug was only mildly toxic.
When all of the p450 enzymes were killed (inactivated) by exposing the cells briefly to
carbon monoxide (CO), the drug was even more toxic. What was going on?
C. In testing for DILI in vivo, it is common to monitor blood for an aminotransferase (e.g.,
ALT, AST, etc.), but this fails when the drug causes cholestasis, and testing for alkaline
phosphatase is the preferred assay. Please explain.

Question 2
When thinking about toxicity, we can think about drug metabolizing enzymes that a xenobiotic
encounters during both phase I and phase II of metabolism, which generally consists of hydrolysis,
reduction, oxidation and conjugation reactions. If the drug encounters an enzyme that can convert
xenobiotics to reactive electrophilic metabolites, these metabolites can therefore react with
nucleophiles in the cell such as DNA or proteins and covalently bind, leading to toxicity. The
enzyme most often associated with the process of generating reactive electrophiles is cytochrome
p450. My approach therefore for this problem will be to analyze how many sites in each drug can be
recognized by a metabolic enzyme and subsequently converted to an electrophile.
A)Structures and approach are attached on a separate PDF file. I outline the possible reactive site in
each molecule and which I think will form the most reactive intermediates. Hypo1 can form the
following potent metabolites nitrogen cation electrophile, a sulfinic acid, an ortho-quinone and an
epoxide group and a ketone intermediate. Hypo 2 can form the following potent metabolites: a
para-quinone, an α,β-unsaturated γ-dicarbonyl compound, an epoxide, and a ketone intermediate.
It seems as though Hypo2 could be less toxic than Hypo1. Because you are losing the toxicity
from the heterocyclic tertiary amine oxidation and the sulfur oxidation, but you still have major
quinone toxicity. I would say that the most important electrophile for each structure is phenol
rings which can easily be converted to quinones. Quinones are powerful electrophilic Michael
Acceptors that can react with cellular nucleophiles and form protein adducts. For example,
neurotoxicity associated with Parkinson’s disease can be explained by para-quinone formed from
the oxidation of dopamine, (Labenski et al 2009).
1

B)Diclofenac is an NSAID (or nonsteroidal anti-inflammatory drug) which is used to reduce
inflammation.
This is its chemical structure:
Dicflofenac can get extensively metabolized into well characterized metabolites including
4’-hydroxydiclofenac, 5-hydroxydiclofenac (5 OHdic), 3′-hydroxydiclofenac, 4′,5-
dihydroxydiclofenac, and 3′-hydroxy-4′
methoxydiclofenac. 4’ and 5’-hydroxydiclofenac are known to form highly reactive quinone
imines.
Without cytochrome p450, usually diclofenac is less toxic in vitro because there is no formation
of the reactive metabolites. In this case, however, diclofenac has some toxicity associated with
itself. Diclofenac in vitro has been shown to impair ATP synthesis by the mitochondria, (Bort et
al 1999). Impairing ATP synthesis would essentially cause cell death. While diclofenac’s
metabolites can also impair ATP synthesis to some extent, usually the metabolites are present
with some concentration of the parent molecule as well. Here, we just have a large concentration
of diclofenac that can all react with the mitochondria and essentially is not titrated away by a
CYP.
On the other hand, diclofenac could be metabolized by another enzyme in the cell. UDPGTs,
for example, have been shown to react with diclofenac to produce a reactive electrophile that
can form protein adducts, (from Prof. Tannenbaum’s Drug Metabolism II Lecture). Perhaps,
we do not normally observe as much of this reaction because diclofenac binds with a higher
affinity to CYPs than UGTs, but in the absence of CYP we can observe this affect, assuming
CHO cells express UGTs.

C) Cholestasis is a condition where bile cannot flow from the liver to the duodenum. In testing
for Drug Induced Liver Injury, according to the FDA’s standard of Hy’s Law, a drug that shows
hepatocellular injury will show greater than 3-fold elevation of ALT or AST above the normal
and greater then 2x the upper limit of normal for total bilirubin levels. However, since cholestasis
is an obstructive condition, it can also cause increases in serum bilirubin levels but it has not been
characterized to cause high elevation of ALT or AST. Therefore, by just testing for ALT and AST,
cholestasis will be overlooked. However, testing for ALP levels is more specific to cholestasis
over general DILI. Since in cholestasis, the bile ducts can become blocked, ALP levels will rise
in the serum because it is expressed in the edges of the cells that join together to form the bile
ducts. In general, hepatocellular injury induced necrosis can vastly increase the serum levels of
ALT and AST. However, cholestasis is functionally a blockage disorder, caused by inhibition of a
transporter such as BSEP. ALT and AST will not be majorly transported into the serum during
cholestasis.
Sources:
Bort, R. et al. “Diclofenac Toxicity to Hepatocytes: A Role for Drug Metabolism in Cell
Toxicity.” Pharmacology. (1999): 288(1)
Regan, SL. Et al. “Acyl glucuronides: the good, the bad and the ugly.” Biopharmaceutics
and Drug Disposition. (2010): 31(7)
http://labtestsonline.org/understanding/analytes/alp/tab/test

Hypoamericillin 1
Hypoamericillin 2
S
HO
N O
OH
O
H
F
HO
O
OH
O
HN
O
OH O
F
F
epoxide
poxide
O-
Dealkyl
-ation
Oxidation
E
formation
to -c=O, cOOH
Oxidation to -c=O
Oxidation to Carboxylic Acid,
ketone intermediate
OCH3
Oxidation to Carboxylic Acid,
ketone intermediate
OCH3
F
Dealkylation or Oxidation
Oxidation to -c=O, cOOH
N-Dealkylation
Oxidation to -C=O
oxidation
N N
Epoxide
formation
N-Dealkylation
Blue Star – Standard Hydroxylation by CYP450
Reactions in bold font lead to possible toxic intermediates
Epoxide
formation

Hypoamericillin 2
Toxicity
Para"quinone

Hypoamericillin 2
Electrophile

Hypoamericillin 2
Possible toxicity
Epoxide
electrophile

Hypoamericillin 1
Electrophile
Toxicity
Hypoamericillin 1

S
N O
OH
P450
N N
Hypoamericillin 1
OCH3
F
F
O
O
Ortho"Quinone
Oxidative Stress
DNA Damage

N N
HO
O
S
OH
HO
F
N
P450
Hypoamericillin 1
OCH3
F
O
Possible toxicity
Epoxide
electrophile

Terminal Acetylene Groups:
S
HO
N
OH
HO
F
OCH3
F
HO
N N
O
OH
O
HN
O
OH O
OCH3
F
F
From Professor Tannenbaum's Lecture Notes:
Hypoamericillin 1

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