Here's a question I've encountered...

[Phloston]

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So here's a question I got from Robbin's Review of Pathology:

In an experiment, the effects of xenobiotic activation of the compound benzo[a]pyrene, a chemical carcinogen present in cigarette smoke, are studied in various tissues. Investigators determine that formation of a secondary metabolite, which binds covalently to DNA, increases the frequency of lung cancers. Which of the following is the most likely metabolic pathway for generation of this xenobiotic?

A) Biomethylation
B) Cytochrome P-450
C) Flavin-containing monooxygenase
D) Glucuronidation
E) Glutathione
F) Peroxidase-dependent cooxidation

When I saw this question, I honestly had no idea.

The answer is B.

Here is the explanation given from Robbin's:

The cytochrome P-450 dependent monooxygenase, or mixed function oxidase, system is found in SER and normally functions to detoxify endogenous hormones. However, it can also serve to activate xenobiotics to carcinogens. Biomethylation by environmental microorganisms of inorganic mercury dumped into bodies of water can lead to accumulation of toxic methyl mercury, which can work its way up the food chain to humans. Flavin-containing monooxygenase found in ER can oxidize nicotine. Glucuronidation can convert naphthylamine to a carcinogen that causes urinary tract cancers. Reduced glutathione helps to break down free radicals produced by oxygenase systems such as P-450; xenobiotic metabolism can deplete glutathione and enhance free radical cellular injury. The peroxidase-dependent cooxidation pathway can metabolize 2-naphthylamine to a carcinogen that causes urinary tract cancers.

I thought this was interesting because FA briefly mentions Clara cells as the detox centers of the lung. I had also encountered in QBank that they are the site of P-450 metabolism in the lung. However, I hadn't known the P-450 detox was what also activates carcinogens in the lung. It just slipped my mind, because when I hear P-450, I immediately think liver, not lung.

I'm only posting this because this is the first real applicable link to Clara cells out of any question I've encountered so far.

Not to mention, the nicotine and urinary cancer tid bits are also good wtf-question info.

 

[AndyRSC]

This seems like a straight Phase I vs Phase II metabolism question, where Phase I is conducted by P-450 and yields metabolites that are sometimes active and/or toxic. You could know nothing else to answer this question.

 

[DroptheBop]

Good points.
Just FYI, there's a question that's pretty similar to that in Uworld that I'm sure you'll see in November or whenever you get around to doing it (1797 if you're looking for it)
Also, aren't clara cells involved with bronchial and bronchioalveolar adenocarcinoma?

 

[Phloston]

This seems like a straight Phase I vs Phase II metabolism question, where Phase I is conducted by P-450 and yields metabolites that are sometimes active and/or toxic. You could know nothing else to answer this question.

P-450 phase-I reactions are oxidation, reduction and/or hydrolysis. Both choices C and F are also oxidation-based mechanisms, so their resultant products could equally be deleterious. There's no reason to just assume P-450 here, considering choice C does occur in the lung as well.

 

[RedSoxSuck]

P-450 phase-I reactions are oxidation, reduction and/or hydrolysis. Both choices C and F are also oxidation-based mechanisms, so their resultant products could equally be deleterious. There's no reason to just assume P-450 here, considering choice C does occur in the lung as well.

Since we are talking about p450, does anyone have a list of drugs which are metabolized by p450? Not talking about inducers or inhibitors of p450.

So far i have only come across the following drugs which are metabolized by p450:
Warfarin, Phenytoin, metapropolol, quinidine, theophylline.

 

[beeitchness]

Since we are talking about p450, does anyone have a list of drugs which are metabolized by p450? Not talking about inducers or inhibitors of p450.

So far i have only come across the following drugs which are metabolized by p450:
Warfarin, Phenytoin, metapropolol, quinidine, theophylline.

You sure you want to go there? There's a ton obviously...

Under the "Substrates" heading: http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx

 

[RedSoxSuck]

You sure you want to go there? There's a ton obviously...

Under the "Substrates" heading: http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx

LOL..Well, i meant the most common ones.

 

[futuredoctor10]

Since we are talking about p450, does anyone have a list of drugs which are metabolized by p450? Not talking about inducers or inhibitors of p450.

So far i have only come across the following drugs which are metabolized by p450:
Warfarin, Phenytoin, metapropolol, quinidine, theophylline.

That would be a good addition to FA 2013... in the section on P450 inhibitors/inducers.

I think warfarin, phenytoin are big ones, which you mentioned.

Also oral contraceptives, statins, cyclosporine are all metabolized by P450s.
Ethanol is metabolized by CYP 2E1.

 

[Kaputt]

LOL..Well, i meant the most common ones.

Warfarin is classic because there are obvious implications if you have too much or too little. But they can do it for lots of drugs, and it's not worth memorizing a ton because: for most drugs, usually the clinical context and toxicity (or deficiency) symptoms will make it obvious what the drug is, and you have to pick the inducer or inhibitor of P-450 that messed everything up.

The real deal was pretty fair on this stuff for my exam.

 

[zof881]

Andy's got the right of it. I've come across a couple questions about the P450 monooxygenase system making carcinogens "active". I think the general concept here being tested is just realizing that somethings (xenobiotics, chemicals in smoke etc) aren't a carcinogen till the P450 system goes to work on it.

 

[ButterIsMagical]

Yeah, there's a thing in FA saying that cyp450 usually activates while phase 2 rxns usually inactivate. BUT, I've been wondering what Clara cells do for, like, 2 years (no joke), so I'm really happy you posted this.

Also what's funny is that olds lose phase 1 metabolism as they age -- does that mean I should start smoking when I'm 60? Because they I won't activate the main carcinogen? I can't wait until I'm old.

 

[Phloston]

Ethanol is metabolized by CYP 2E1.

Nice. That's one of the two CYP tidbits to know. EtOH MEOS = CYP2E1.

The other: my relative at HMS got a question on his exam asking about the metabolism of warfarin. The tidbit here is that most warfarin (left-handed) is CYP2C9-metabolized, not 3A4-.

Also what's funny is that olds lose phase 1 metabolism as they age -- does that mean I should start smoking when I'm 60? Because they I won't activate the main carcinogen? I can't wait until I'm old.

That gave me the levity I needed.