Does caffeine’s Metabolization phenotype can influence coffee drinking habit? International Forum on Coffee and Health effects 2nd International Summit on clinical pharmacy December 2-3 2014, San Francisco, California, USA Roseane M. M. Santos, PhD, Associate Professor Dept. Pharmaceutical Sciences, School of Pharmacy

Overview Coffee consumption and risk of development of diseases Caffeine metabolism and genetic polymorphisms Our hypothesis CYP 1A2 Phenotype and coffee drinking habit What is coming up?

Coffee consumption and risk of development of diseases Coffee is the major SOURCE of caffeine in the American DIET For DECADES has been blamed for ALL SORTS of health PROBLEMS Cardiovascular : HYPERTENSION, MIOCARDIAL INFARCTION Neurodegenerative diseases: PARKINSON’s and ALZHEIMER’S VARIOUS CANCERS: liver, breast, colon. All have been proved NOT TO BE TRUE when there is a MODERATE CONSUMPTION : 2-3 CUPS/DAY

We had some questions… It is common to hear that “ I love the smell of coffee but I can’t have it ! It make me feel bad! Why ? Could it be that those individuals are more ‘sensitive’ to the effects of coffee than the general population? What makes them ‘more sensitive’? Are those the one’s that drink decaf coffee?

Our hypothesis Individuals that are more sensitive to coffee/caffeine effects EITHER DRINK DECAFFEINATED COFFEE OR DON’T DRINK COFFEE/CAFFEINE AT ALL BECAUSE THEY TEND TO ACCUMULATE HIGHER LEVELS OF CAFFEINE IN THE CIRCULATION, As consequence they present an EXACERBATED effect from ‘normal’ doses of caffeine (coffee)

CYP 450 Enzymes family

Caffeine metabolism 95% metabolized by CYP 1A2 N-demethylation What happens if metabolism is impaired? Answer: CAFFEINE is ACCUMULATED!

CYP 1A2 genetic polymorphisms Gene is located at 15q24.1 Polymorphic allele is due to a SNP located in the 5'- noncoding promoter region of the gene

CYP 1A2 Polymorphisms CYP 1A2*1A wild type allele CYP1A2*1F variant allele It is due to a substitution of a base in the non- coding region of the CYP1A2 gene An A C substitution at position 734 (-163 CA ) Has the effect of DECREASING the enzyme inducibility.

CYP 1A2 Phenotype and coffee drinking habit CYP1A2 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. It is most active in catalyzing N-hydroxylation or N- dealkylation reactions. Individuals who are HOMOZYGOUS for the CYP1A2*1F allele are 'slow' caffeine metabolizers. Consequence: those individuals ACCUMULATE caffeine in the body!

Pilot study 8 hours minimum of fasting 2 blood samples collected 15 healthy young volunteers 8 hours minimum of fasting 2 blood samples collected Zero hour 45-60 minutes after ingestion of 1 cup of coffee a Standard breakfast was provided Caffeine and Chlorogenic acids blood levels were determined Coffee contents of caffeine and brief survey collected Blood cells harvested and CYP 1A2 genotype determined

Study results Our volunteers Summary 11/15 genotypes obtained All 3 possible genotypes found 8/11 WILD TYPE HOMOZYGOUS 2/11 HETEROZYGOUS 1/11 VARIANT TYPE HOMOZYGOUS Fast metabolizers had caffeine Plasma levels of zero-0.67mg/L Slow metabolizer had highest levels of caffeine (1.11mg/L) Survey on coffee consumption NOT conclusive

What is coming? The Coffee and Caffeine Genetics Consortium Purpose: to better understand the controversial data found on coffee/caffeine effects from habitual coffee consumption A trans-ethnic GENOME-WIDE meta-analysis were done between 30,062 from European and 7,964 from African-American ancestry presenting top SNPs 8 loci met significance and 6 of them were LOCATED or NEAR genes of PK/PD of caffeine!

Questions?

Major coffee constituents Coffea arabica (%) Coffea robusta (%) CAFFEINE 1.0 - 1.5 3.0 - 4.5 MINERALS (K, Fe, Ca, OTHERS) 3.0 - 4.0 4.0 - 5.0 CHLOROGENIC ACIDS (total) 5.0 - 7.0 7.0 - 9.0 SUGARS 50 – 55 35 – 45 LIPIDS 10 - 20 - 15 AMINOACIDS 1.0 1.5 TRIGONELLINE 0.75 NIACIN or VITAMIN PP 0.5 OTHERS 10 - 20 15 - 25

Number of drugs metabolized per CYP Preissner SC, Hoffmann MF, Preissner R, Dunkel M, et al. (2013) Polymorphic Cytochrome P450 Enzymes (CYPs) and Their Role in Personalized Therapy. PLoS ONE 8(12): e82562. doi:10.1371/journal.pone.0082562 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082562